Index for Lymphoma

Index for Lymphoma

Jeffrey Dach MD

Left Image Cover of Book, Cracking Cancer Toolkit

p 20

Ibrutinib is Bruton’s
tyrosine kinase inhibitor, a targeted pathway drug that inhibits the B-cell receptor and has revolutionized lymphoma treatment.

p 36 In 2003, Drs. Peter Gout et al. studied the
effect of an old rheumatology drug, sulfasalazine
(Azulfidine®), on the tumor microenvironment
of lymphoma.

sulfasalazine

31) Gout, Peter W., Chris R. Simms, and May C.
Robertson. “In vitro studies on the lymphoma
growth-inhibitory activity of sulfasalazine.” Anticancer
drugs 14.1 (2003): 21-29.

Itraconazole

p 58 In Blood (2016), Dr. Juan J. Gu et al. studied
chemotherapy resistant NHL (Non-Hodgkin’s
Lymphoma) cell lines in vitro and found that
itraconazole disrupts HK2 from the mitochondria
and enhances the efficacy of chemotherapy
agents.

41) Gu, Juan J., et al. “Itraconazole, an Oral Antifungal
Drug, Is Active in Chemotherapy Resistant B-Cell Non-
Hodgkin Lymphoma and Enhances the Anti-Tumor
Activity of Chemotherapy Agents.” Blood. (2016):
5138-5138.

Metfromin / DCA / Venetoclax synergy

p 57 In 2016, Dr. Juliana Velez et al. found that
metformin used in combination with DCA,
synergizes with venetoclax, a new oncology
drug approved for use in lymphomas known
to express high levels of the BCL-2 protein that
inhibits apoptosis.

p 60
Anti-Cancer Effects of DCA on Various
Cancers:
• Non-Hodgkin’s lymphoma (110–111)

p 61
Case Report “Durable Complete
Remission” of NHL with DCA
Dr. Stephen Strum (2012) et al. report on
a 52-year-old male (TM) who had a 6 year
history of B-Cell Lymphoma

110) Strum, Dana F. “Non-Hodgkin’s lymphoma reversal
with dichloroacetate.” Journal of oncology 2010
(2010).

111) Strum, Stephen B., et al. “Case report: Sodium
dichloroacetate (DCA) inhibition of the “Warburg
Effect” in a human cancer patient: complete response
in non-Hodgkin’s lymphoma after disease progression
with rituximab-CHOP.” Journal of bioenergetics and
biomembranes 45.3 (2013): 307-315.

120) Kumar, Ajay, Shiva Kant, and Sukh Mahendra
Singh. “Novel molecular mechanisms of antitumor
action of dichloroacetate against T cell lymphoma:
Implication of altered glucose metabolism, pH homeostasis
and cell survival regulation.” Chemico-biological
interactions 199.1 (2012): 29-37.

141) Djordjević, Mladen, and Ivan Petković.
“Dichloroacetate-Induced Neuropathy in High Grade
Follicular Lymphoma Patient.” Acta Medica Medianae
58.1 (2019): 102-105

p 72 Lymphoma in Animal Model of Chronic Stress

p 72 In 2012, Dr. Donald Lamkin et al. used a lymphoblastic
leukemia model in mice undergoing
restraint stress to answer the question, “Does
chronic stress cause cancer?” Dr. Lamkin’s 2012
study, published in Brain Behavior, showed that
mice suffering from restraint stress had accelerated
progression of lymphoma compared to
controls. (8)

p 80
Immunosuppressive Effect of
Beta-Adrenergic Signaling

In 2017, Dr. Michael Nissen et al. studied
beta-adrenergic signaling in a mouse model of
lymphoma, finding that chronic beta-adrenergic
signaling enhanced tumor immune evasion
by inhibiting CD8+ T cell response.

18) Nissen, Michael D., Erica K. Sloan, and Stephen
R. Mattarollo. “β-adrenergic signaling impairs antitumor
CD8+ T-cell responses to B-cell lymphoma immunotherapy.”
Cancer immunology research 6.1 (2018):
98-109.

p 91 Combination of ALA and LDN: Case
Report of Metastatic Pancreatic Cancer
In 2009, Dr. Burton Berkson reported a
series of remarkable cancer remissions using
the combination of ALA and LDN in pancreatic
cancer and B-cell lymphoma. (23–25)

The patient sought medical care with Dr.
Berkson, who started treatment with intravenous
ALA, 300 to 600 mg twice a week, and
LDN 4.5 mg at bedtime. Supplements given
were: oral ALA (600 mg/d), selenium (200
mcg twice daily), and silymarin (300 mg, four
times a day).

p 92

Case Report B-Cell Lymphoma Remission
A 61-year-old male with progressive follicular
lymphoma who declined conventional chemotherapy
sought medical care at Dr. Berkson’s
clinic. The patient was treated solely with nine
intravenous (IV) ALA treatments and was continued
on oral LDN 4.5 mg nightly. Six months
later, the enlarged lymph nodes had resolved,
and the patient remained in remission for
another year, after which he was lost to follow-
up. (25)

25) Berkson, Burton M., Daniel M. Rubin, and Arthur
J. Berkson. “Reversal of signs and symptoms of a B-cell
lymphoma in a patient using only low-dose naltrexone.”
Integrative cancer therapies 6.3 (2007): 293-296.

Melatonin

p 94 Dr. Reiter et al. (2014) further state:
Melatonin behaves as a “smart killer,” i.e.,
modulating anti-apoptotic processes in
normal cells, and triggering pro-apoptotic
signals in cancer cells… indeed, melatonin
induces apoptosis in several types of
tumors: colon cancer cells, hepatocarcinoma,
glioma and neuroblastoma, Ehrlich
ascites carcinoma cells, lymphoma, leukemia
cells, etc. (62–64)

p 97
Melatonin has antiproliferative, anti-angiogenic,
pro-apoptotic and immunomodulatory
effects on many cancer types including:
• Hodgkin’s lymphoma (85)
• Hematologic neoplasms, B Cell
Lymphoma (86–88)

p 97

In a 2014 Journal of Cancer report, Dr. Zhihui
Min et al. remark that
PQQ could induce apoptosis in human promonocytic
leukemia U937 and lymphoma
EL-4 cells. The underlying mechanism might
be relevant to the increase of intracellular
reactive oxygen species (ROS) and depletion
of glutathione. (111)

Melatonin
p 102
85) Yan, Gege, et al. “Melatonin triggers autophagic
cell death by regulating RORC in Hodgkin lymphoma.”
Biomedicine & Pharmacotherapy 123 (2020): 109811.

87) Trubiani, Oriana, et al. “Melatonin provokes cell
death in human B‐lymphoma cells by mitochondrialdependent
apoptotic pathway activation.” Journal of
pineal research 39.4 (2005): 425-431.

p 106
Lymphomas Are Sensitive

Lymphoma cells are especially sensitive
to IV vitamin C at low serum concentrations
(LD50 of 0.5 mmol/L). (4–5) Downregulating
the dual anti-oxidant system with auranofin,
which inhibits the thioredoxin reductase system,
and a second agent such as celecoxib,
which attenuates glutathione levels, potentiates
the cytotoxic effects of vitamin C. (6–8)

Auranofin / IV Vitamin C synergy

p 108
Auranofin is a gold-containing rheumatology
drug used for many years for arthritis patients.
It has been repurposed as an anti-cancer drug.
Auranofin inhibits the thioredoxin reductase
system, which increases ROS in the cancer cells.
(6–7) The combination of IV ascorbate (vitamin
C) and auranofin was found to be “strongly”
synergistic in vitro for malignant B cells (lymphoma)
and in a mouse xenograft breast cancer
model as reported by Drs. Agnieszka Graczyk
et al. (2019) and Dr. Elie Hatem et al. (2018).
(31–32)

p 109
This explains the ability of doxycycline to induce clinical remission and
in some cases “cure” for patients with periorbital
and gastric MALT lymphomas. (33–34)

33) Han, Jae Joon, et al. “Long-term outcomes of
first-line treatment with doxycycline in patients with
previously untreated ocular adnexal marginal zone B
cell lymphoma.” Annals of hematology 94.4 (2015):
575-581.

34) Raderer, Markus, et al. “Antibiotic treatment as
sole management of Helicobacter pylori-negative
gastric MALT lymphoma: a single center experience
with prolonged follow-up.” Annals of hematology 94.6
(2015): 969-973.

p 110

Safety of High-Dose IV Vitamin C
In 2014, Dr. Hiroshi Kawada et al. evaluated
the safety of IV vitamin C in a phase one clinical
trial of three patients with B-cell lymphoma
given 75 grams of ascorbate intravenously.
Serum ascorbate levels exceeded 15 mMoles/L
with no adverse effects. (11).

10) Kawada, Hiroshi, et al. “Phase I Clinical Trial
of Intravenous L-ascorbic Acid Following Salvage
Chemotherapy for Relapsed B-cell non-Hodgkin’s
Lymphoma.” The Tokai journal of experimental and
clinical medicine 39.3 (2014): 111-115.

11) Kawada, Hiroshi, et al. “Phase I Clinical Trial
of Intravenous L-ascorbic Acid Following Salvage
Chemotherapy for Relapsed B-cell non-Hodgkin’s
Lymphoma.” The Tokai journal of experimental and
clinical medicine 39.3 (2014): 111-115.

p 117)
A clinical trial safety study on relapsed
B-cell lymphoma patients receiving 75 grams
of vitamin C intravenously reported no adverse
effects. (10)

p 121)

Statin drugs such as simvastatin have standalone
anti-cancer activity by activating the
intrinsic apoptosis pathway. (30) In vitro studies
show statin drugs induce apoptosis in B-cell
lymphoma via suppression of the mevalonate
pathway. (31)
31) Qi, X. F., et al. “HMG-CoA reductase inhibitors
induce apoptosis of lymphoma cells by promoting ROS
generation and regulating Akt, Erk and p38 signals via
suppression of mevalonate pathway.” Cell Death &
Disease 4.2 (2013): e518.

p 122)

Doxycycline for Lymphoma

In 2015, Drs. David Barbie and Brian
Kennedy summarized the preclinical work
of Dr. Mary Pulvino et al. on doxycycline for
B-cell lymphoma. Doxycycline accumulates
in lymphoma cells in high concentrations.
Summarizing the work of Pulvino, Drs. Barbie
and Kennedy wrote: Notably, doxycycline was also effective at
inhibiting the growth of DLBCL [Diffuse
Large B-cell Lymphoma] xenografts at
physiologically achievable doses…. (38–39)
Others have written extensively on the use
of doxycycline as a potential anti-CSC agent and
radiation sensitizer. (40–42)

p 124)
Doxycycline for MALT Lymphoma
(Mucosa-Associated Lymphoid Tissue)
58) Kuo, Sung-Hsin, et al. “Novel Insights of
Lymphomagenesis of Helicobacter pylori-Dependent
Gastric Mucosa-Associated Lymphoid Tissue
Lymphoma.” Cancers 11.4 (2019): 547.
59) Raderer, Markus, et al. “Antibiotic treatment as
sole management of Helicobacter pylori-negative
gastric MALT lymphoma: a single center experience
with prolonged follow-up.” Annals of hematology 94.6
(2015): 969-973.

p125)
Doxycycline is a fast, safe, and active therapy
for Cp DNA-positive OAL [DNA-positive
for Chlamydia, Ocular Adnexal Lymphoma]
that was effective even in patients with
multiple failures involving previously irradiated
areas or regional lymphadenopathies.
(61–64)
61) Ferreri, Andrés JM, et al. “Bacteria-eradicating
therapy with doxycycline in ocular adnexal MALT lymphoma:
a multicenter prospective trial.” Journal of the
National Cancer Institute 98.19 (2006):1375-1382.
62) Han, Jae Joon, et al. “Long-term outcomes of
first-line treatment with doxycycline in patients with
previously untreated ocular adnexal marginal zone B
cell lymphoma.” Annals of hematology 94.4 (2015):
575-581.
63) Husain, Amina, et al. “Meta–analyses of the association
between Chlamydia psittaci and ocular adnexal
lymphoma and the response of ocular adnexal lymphoma
to antibiotics.” Cancer 110.4 (2007): 809-815.
64) Abramson DH, Rollins I, Coleman M. Periocular
mucosa-associated lymphoid/low grade lymphomas:
treatment with antibiotics. Am J Ophthalmol.
2005;140:729–730.

p 125)

Doxycycline Synergy with
Hydroxychloroquine

Coxiella burnetii is an intracellular
gram-negative bacterial pathogen which causes
Q fever, and is associated with B-cell lymphoma.
In 2018, Drs. Cléa Melenotte and Didier Raoult
reported a patient whose C. burnetti associated
B-cell lymphoma responded to the combination
of doxycycline and hydroxychloroquine (autophagy
inhibitor). (65)
65) Melenotte, Cléa, and Didier Raoult. “Pro-apoptotic
effect of doxycycline and hydroxychloroquine on B-cell
lymphoma induced by C. burnetii.” Oncotarget 9.2
(2018): 2726.

p 127

39) Pulvino, Mary, et al. “Inhibition of COP9-
signalosome (CSN) deneddylating activity and tumor
growth of diffuse large B-cell lymphomas by doxycycline.”
Oncotarget 6.17 (2015): 14796.

p 132
Curcumin Suppresses Cyclin D1
in Mantle Cell Lymphoma

In 2012, Dr. Zainul Hasanali et al. studied
curcumin in a B-cell lymphoma (mantle cell)
model, finding that curcumin inhibits nuclear
factor kappa B (NF-κB) activation and downregulates
cyclin D1, thereby inducing apoptosis.
There was synergy with bortezomib, a new
protease inhibitor drug used for hematologic
malignancies. (14)

14) Hasanali, Zainul, Kamal Sharma, and Elliot Epner.
“Flipping the cyclin D1 switch in mantle cell lymphoma.”
Best Practice & Research Clinical Haematology
25.2 (2012): 143-152.

15) Shishodia, Shishir, et al. “Curcumin (diferuloylmethane)
inhibits constitutive NF-κB activation, induces
G1/S arrest, suppresses proliferation, and induces
apoptosis in mantle cell lymphoma.” Biochemical
pharmacology 70.5 (2005): 700-713.

16) Singh, Amareshwar TK, et al. “Curcumin nanodisk-
induced apoptosis in mantle cell lymphoma.”
Leukemia & lymphoma 52.8 (2011): 1537-1543.
17) Tadmor, Tamar, and Aaron Polliack. “Mantle cell
lymphoma: curcumin nanodisks and possible new concepts
on drug delivery for an incurable lymphoma.”
Leukemia & lymphoma 52.8 (2011): 1418.

p 148)
120) Gunn, Ellen J., et al. “The natural products parthenolide
and andrographolide exhibit anti-cancer
stem cell activity in multiple myeloma.” Leukemia &
Lymphoma 52.6 (2011): 1085-1097.

p 151
Sulfasalazine has been studied in other cancer
cell types, including:
Head and neck cancer (10)
• B-cell lymphoma (11–12)

11) Bebb, G., et al. “Sulfasalazine, inhibits growth of
mantle cell lymphoma (MCL) cell cultures via cyst (e)
ine starvation and delays tumour growth in a newly
developed murine MCL model.” Blood. Vol. 102. No.
11. 2003.

12) Gout, Peter W., Chris R. Simms, and May C.
Robertson. “In vitro studies on the lymphoma
growth-inhibitory activity of sulfasalazine.” Anticancer
drugs 14.1 (2003): 21-29.

p 152
Cystine Supplied by Fibroblasts
in the Micro-Environment

In 2003, Dr. Peter Gout et al. studied the
effect of sulfasalazine on xc– deficient mouse
model of T cell lymphoma. These lymphoma
cells were genetically modified to knock out
the active transport of cystine, and should have
been non-viable. However, they grew quite
well because of fibroblasts in the micro-environment
were “hijacked” to feed cystine to
the lymphoma cells.

p 155)

The Wnt PATHWAY—Key to
Cancer Stem Cell Destruction

Cancer Cells upregulate the Wnt Pathway—
Wnt ON: This is BAD.

The Wnt pathway controls embryonic development
and cell proliferation and is massively
upregulated in CSCs. In 2015, Dr. Mathur
reports that inhibiting the Wnt pathway is the
key to killing CSCs in a B-cell lymphoma model.
(79)

79) Mathur, Rohit, et al. “Targeting Wnt pathway in
mantle cell lymphoma-initiating cells.” Journal of
hematology & oncology 8.1 (2015): 63.

p 156)
100-Fold Elevated Expression of
Wnt Target Genes in Stem Cells

In 2015, Dr. Rohit Mathur et al. from MD
Anderson studied B-cell lymphoma, finding
that the mantle cell lymphoma (MCL) CSCs
have an elevated expression of Wnt target
genes greater than 100-fold compared with
non-stem cells. The authors also reported that
blocking the Wnt pathway kills CSCs in MCL. Dr.
Mathur et al write:
The high rate of MCL relapse after initial
apparent clinical remissions achieved with
conventional chemotherapy… implicates
a role for chemo-resistant Mantle Cell
Lymphoma –Initiating Cells [stem cells
called MCL-ICs] in relapse. Here we showed
that MCL-ICs [stem cells] have functional
properties of cancer stem cells: high
expression of ALDH, anti-oxidant enzymes,
chemoresistance-associated genes, and
stem cell associated transcription factors,
while still retaining [the gene mutation]
t(11;14) (q13; q32) and overexpression
of cyclin D1 [a proliferation signal].
Our analysis showed that MCL-ICs overexpress
a subset of Wnt ligands and FZD receptors
and that Wnt signaling is activated in
MCL-ICs…. Treatment of primary [mantle
cell lymphoma] MCL cells with Wnt inhibitors
preferentially eliminated MCL-ICs
[initiating cells, stem cells], which was not
achieved with the current chemotherapy
agents vincristine, doxorubicin, or even
with the recently FDA-approved agent
ibrutinib.

p 165)
Pyrvinium exhibits potent anti-cancer activity
as a Wnt pathway inhibitor against the following
CSC lines:

• Blast-phase chronic myeloid leukemia
stem cells (11–12)
• Lymphoma (13)

p 168

Pyrvinium Blocks Glutathione
Uptake from Tumor
Micro-Environment-Lymphoma

In 2015, Dr. Keiki Sugimoto et al. developed
a high through-put drug-screening system
using patient-derived xenografts of lymphoma
transplanted into immunodeficient mice. Using
a library of 2613 off-patent drugs, they found
that pyrvinium showed the highest activity
with “strong anti-tumor activity.” This was confirmed
with in vivo studies. The mechanism
was related to inhibition of glutathione supply
from stromal cells in the micro-environment
to the lymphoma cells. Dr. Sugimoto and colleagues
write:

We extensively investigated its [pyrvinium’s]
mechanism of action and found that
it inhibited glutathione supply from stromal
cells to lymphoma cells. (28)

28) Sugimoto, Keiki, et al. “Discovery of a drug targeting
microenvironmental support for lymphoma cells
by screening using patient-derived xenograft cells.”
Scientific reports 5 (2015): 13054.

13) Xiao, Meifang, et al. “Pyrvinium selectively induces
apoptosis of lymphoma cells through impairing mitochondrial
functions and JAK2/STAT5.” Biochemical and
biophysical research communications 469.3 (2016):
716-722.

p 189

In B-Cell lymphoma, Myc gene amplification
or overexpression might be related to a more
aggressive, blastoid variant. (29)

p 189
Indeed, in 2015, Dr. Shuhua Yi et al. studied a
series of mantle B-cell lymphoma patients with
c-Myc overexpression, writing:
Intensive chemotherapy, such as
HyperCVAD/MA ± R [standard chemotherapy
protocol for lymphoma] did
not improve the survival of [lymphoma
patients] with a c-Myc abnormality, and a
new treatment strategy should be developed.
(30)

p 193)

Metformin Inhibits B-Cell Lymphoma

Dr. W.Y. Shi et al. reported in Cell Death
(2012) that AMPK activity is completely lost
in lymphoma cells and is restored by metformin,
which blocks lymphoma cell growth via
inhibition of the mTOR pathway. Remarkably,
metformin blocked tumor growth in murine
lymphoma xenografts at a concentration of 10

50) Shi, W. Y., et al. “Therapeutic metformin/AMPK
activation blocked lymphoma cell growth via inhibition
of mTOR pathway and induction of autophagy.” Cell
death & disease 3.3 (2012): e275-e275.

p 217
Downregulates the PI3K/
Akt/mTOR Pathway

Dr. Dandan Yu (2018) studied the effect of
pterostilbene on mantle cell lymphoma cells,
finding attenuation of cancer cell progression
by downregulation of the PI3K/Akt/mTOR
pathway. (62)

62) Yu, Dandan, et al. “Targeting the PI3K/Akt/mTOR
signaling pathway by pterostilbene attenuates mantle
cell lymphoma progression.” Acta biochimica et biophysica
Sinica 50.8 (2018): 782-792.

64) Kong, Yuanyuan, et al. “Pterostilbene induces
apoptosis and cell cycle arrest in diffuse large B-cell
lymphoma cells.” Scientific Reports 6 (2016): 37417.
65) Peck, Connor J., Michelle H. Townsend, and
Kim L. O’Neill. “Resveratrol and pterostibene selectively
chemosensitize Burkitt’s lymphoma cells to
5-Fluorouracil.” (2017): 252-252.

p 238
Cannabinoids have been studied in these
cancer cell lines:

• Leukemia (22)
• Mantle cell lymphoma (23)

23) Flygare, Jenny, et al. “Cannabinoid receptor ligands
mediate growth inhibition and cell death in mantle cell
lymphoma.” FEBS letters 579.30 (2005): 6885-6889.

p 244)

In Blood (2008), Dr.
Claudia Schöllkopf reported that patients who
tested positive for Borrelia antibodies had a
four times greater risk of mantle cell lymphoma.
(2)

p 246
Lymphoma Associated with
Coxiella Brunetti, Q Fever

About one fifth of human cancers are linked
to infection with a viral or bacterial organism

p 247
Pyrvinium has striking anti-cancer activity,
active against blast cell leukemia, lymphoma
and breast cancer. (39–42)
39) Xiao, Meifang, et al. “Pyrvinium selectively induces
apoptosis of lymphoma cells through impairing mitochondrial
functions and JAK2/STAT5.” Biochemical and
biophysical research communications 469.3 (2016):
716-722.

p 255

28) Melenotte, Cléa, and Didier Raoult. “Pro-apoptotic
effect of doxycycline and hydroxychloroquine on B-cell
lymphoma induced by C. burnetii.” Oncotarget 9.2
(2018): 2726.

39) Xiao, Meifang, et al. “Pyrvinium selectively induces
apoptosis of lymphoma cells through impairing mitochondrial
functions and JAK2/STAT5.” Biochemical and
biophysical research communications 469.3 (2016):
716-722.

p 264

Artemisinin-Allicin (Garlic) Synergy
Allicin (diallyl thiosulfinate) the active ingredient
in garlic, has known anti-cancer effects.
Allicin induces caspase-mediated apoptosis in
lymphoma and other cancers. Dr. Wei Jiang et
al. reported in 2013 on the synergistic combination
of artesunate (artemisinin derivative)
with allicin, which increased the anti-cancer
effect on osteosarcoma cell lines in vitro and in
vivo. Dr. Jiang’s group also reported on mouse

tumor xenograft studies; these in vivo studies
showed enhanced synergy for the combination
of Allicin and Artesunate. (36)

p 265 sodium butyrate

In a 2006 report, Dr. Ulrike Heider et al.
studied the effect of sodium butyrate on three
Mantle Cell Lymphoma types. Dr. Heider’s
group reported that butyrate induced potent
programmed cell death (apoptosis) of all three
mantle cell lymphoma types in a dose-dependent
manner. (48)

Butyrate is available as a supplement, or as a
butyrate-producing probiotic, both available at
the health food store. A probiotic named clostridium
butyricum is known to produce butyrate.
This is available from Japan in a product
called Miyarisan, available over the counter
(OTC). It is also contained in Probiotic 3 from
Advanced Orthomolecular Research (AOR).

p 267 Sulfasalazine

Sulfasalazine has a long history of use for
inflammatory bowel disease and rheumatoid
arthritis. Its benefits are thought to arise from
its ability to suppress nuclear factor kappa B.
Sulfasalazine is also a potent suppressor of
lymphoma cells on the basis of suppression
of cystine uptake, which impairs anti-oxidant
defense.

Sulfasalazine Lymphoma Model in Mice
Dr. Bebb reported in 2003 that sulfasalazine
inhibits growth of B-Cell lymphoma in a murine
mantle cell lymphoma (MCL) model. (75)
In 2003, Drs. Peter Gout, Chris Simms, and
May Robertson found that sulfasalazine suppressed
90% of lymphoma xenografts in mice,
a remarkable finding. (76)

p 272
In 2014, Dr. Alice Melotti reported that
ivermectin inhibits the Wnt ‐TCF pathway in
cancer cells, further elucidating the molecular
mechanism of cancer cell death. Targeting the
Wnt pathway successfully eliminated cancer
stem cells in a mantle cell lymphoma cell line.
(110-111)

Inflammatory Signals from the Micro-
Environment in Mantle Cell Lymphoma

p 275

In Blood 2012, Dr. Liang Zhang et al. studied
the role of the micro-environment in mantle
cell lymphoma (MCL). Dr. Zhang’s group found
that the inflammatory cytokine IL-6 secreted
by stromal cells in the micro-environment
activated the Jak2/STAT3 and PI3K/Akt pathways
in MCL. Downstream from NF-kB, IL-6 is
a key cytokine for MCL growth and survival,
and inhibiting NF-kB with ART serves to inhibit
IL-6 production by stromal cells in the TME.
This provides a beneficial anticancer effect,
with inhibition of cancer cell growth, increase
in apoptosis, and greater chemo-sensitivity of
cancer cells. (127)
p 278

7) Lepelletier, Yves, et al. “Prevention of mantle lymphoma
tumor establishment by routing transferrin
receptor toward lysosomal compartments.” Cancer
research 67.3 (2007): 1145-1154.

8) Obrador-Hevia, Antònia, et al. “Molecular biology of
mantle cell lymphoma: from profiling studies to new
therapeutic strategies.” Blood reviews 23.5 (2009):
205-216.

27) Hasanali, Zainul, Kamal Sharma, and Elliot Epner.
“Flipping the cyclin D1 switch in mantle cell lymphoma.”
Best Practice & Research Clinical Haematology
25.2 (2012): 143-152.

Allicin in Lymphoma

37) Padilla-Camberos, Eduardo, et al. “Antitumoral
activity of allicin in murine lymphoma L5178Y.” Asian
Pac J Cancer Prev 11.5 (2010): 1241-4.

MELQATONIN FOR lYMHOMA

40) Trubiani, Oriana, et al. “Melatonin provokes cell
death in human B‐lymphoma cells by mitochondrialdependent
apoptotic pathway activation.” Journal of
pineal research 39.4 (2005): 425-431.

48) Heider, Ulrike, et al. “Histone deacetylase inhibitors
reduce VEGF production and induce growth suppression
and apoptosis in human mantle cell lymphoma.”
European journal of haematology 76.1 (2006): 42-50.

59) Bennaceur-Griscelli, Annelise, et al. “High level
of glutathione-S-transferase π expression in mantle
cell lymphomas.” Clinical cancer research 10.9 (2004):
3029-3034.

71) Gout, P. W., et al. “Sulfasalazine, a potent suppressor
of lymphoma growth by inhibition of the x
c-cystine transporter: a new action for an old drug.”
Leukemia (08876924) 15.10 (2001).

75) Bebb, G., et al. “Sulfasalazine, inhibits growth of
mantle cell lymphoma (MCL) cell cultures via cyst (e)
ine starvation and delays tumour growth in a newly
developed murine MCL model.” BLOOD. Vol. 102. No.
11. (2003).

76) Gout, Peter W. “In vitro studies on the lymphoma
growth-inhibitory activity of sulfasalazine.” Anticancer
drugs 14.1 (2003): 21-29.

110) Mathur, Rohit, et al. “Targeting Wnt pathway
in mantle cell lymphoma-initiating cells.” Journal of
hematology & oncology 8.1 (2015): 63.

p 283

127) Zhang, Liang, et al. “Role of the microenvironment
in mantle cell lymphoma: IL-6 is an important
survival factor for the tumor cells.” Blood 120.18
(2012): 3783-3792.

128) Lai, Raymond, et al. “Expression of STAT3 and
its phosphorylated forms in mantle cell lymphoma
cell lines and tumours.” The Journal of Pathology: A
Journal of the Pathological Society of Great Britain and
Ireland 199.1 (2003): 84-89.

137) Våtsveen, Thea Kristin, et al. “Artesunate shows
potent anti-tumor activity in B-cell lymphoma.” Journal
of hematology & oncology 11.1 (2018): 23.

151) Zhao, Xinying, et al. “Artemether suppresses cell
proliferation and induces apoptosis in diffuse large B
cell lymphoma cells.” Experimental and therapeutic
medicine 14.5 (2017): 4083-4090

p 287

Dr.Melotti used a transcriptional reporter assay
for TCF activity driven by Beta-Catenin to test
a collection of 1,040 drugs and small molecules.
Only one agent, ivermectin, perfectly tracked
the gene expression profile induced by blocking
the TCF gene and therefore inhibited the
Wnt pathway. (8)
This has profound significance This has profound significance for anti-cancer stem cell therapy, because blocking the Wnt
pathway is the key to eradicating cancer stem
cells and solving the problem of cancer recurrence
after chemotherapy. For example, blocking
the Wnt pathway in mantle cell lymphoma
preferentially kills the cancer stem cells. (9–10)

p 289

Ivermectin mTOR Inhibitor— Induces Autophagy

Ivermectin degrades the PAK protein, which
then inhibits mTOR, which activates autophagy.
Note: PAK1 is P21-activated kinase

PAK1 signaling is overexpressed and highly
activated in lymphomas, and its inhibition significantly
inhibits cancer cell viability. (27–28)

27) Ong, Christy C., et al. “Targeting p21-activated
kinase 1 (PAK1) to induce apoptosis of tumor cells.”
Proceedings of the National Academy of Sciences
108.17 (2011): 7177-7182.

28) Tian, Tian. “Role of Rac1-Pak pathway in aggressive
b-cell lymphoma.” (2019).

9) Kimura, Yoshizo, et al. “The Wnt signaling pathway
and mitotic regulators in the initiation and evolution
of mantle cell lymphoma: Gene expression analysis.”
International journal of oncology 43.2 (2013): 457-468.

10) Mathur, Rohit, et al. “Targeting Wnt pathway in
mantle cell lymphoma-initiating cells.” Journal of
hematology & oncology 8.1 (2015): 63.

p 298

Immunohistochemically detected p53 and p21
staining on biopsy slides is sufficient to determine
mutated P53 status with disrupted function
in lymphoma cases. (17–20)

301

Niclosamide Effective for Lymphoma

In 2015, Dr. Junaid Ansari et al. studied the
effect of niclosamide on a panel of aggressive
B-Cell lymphoma cell lines (in vitro), finding
effective inhibition of proliferation and induction
of apoptosis at low concentrations of 0.1
microMolar, while sparing normal lymphocytes
that are not affected by the drug. Dr. Ansari et
al. write:

Treatment with niclosamide at doses
as low as 0.1 μM resulted in time- and
dose-dependent apoptosis, cytotoxicity
and inhibition of proliferation in aggressive
lymphoma cell lines. The 50% inhibitory
concentration in a proliferation assay [0.5
to 0.7 microMolar]…. niclosamide showed
significant cytotoxicity in a patient with
mantle cell lymphoma [MCL]. (31)

31) Ansari, Junaid, et al. “Potent Inhibition of the
Growth and Induction of Apoptosis in Lymphoma by
the Anthelminthic Drug Niclosamide: In Vitro Data.
Blood (2015) 126 (23): 5131-5131.

17) Møller, Michael B., et al. “Disrupted p53 function
as predictor of treatment failure and poor prognosis in
B-and T-cell non-Hodgkin’s lymphoma.” Clinical Cancer
Research 5.5 (1999): 1085-1091.

p 320
Fenbendazole for Human
Lymphoma Xenografts
In 2008, Dr. Ping Gao et al. studied the effect
of fenbendazole in human lymphoma mouse
xenografts, finding an “unexpected anti-tumorigenic
effect.” (61)

p 335 Mefipristone

In 2013, Dr. Ji Hoon Jang et al. studied
the effect of mifepristone on (U937) lymphoma
cells, finding reduction in mitochondrial potential,
activation of p38 MAPK, and induction of
mitochondrial apoptosis. Overexpression of
BCL-2 (anti-apoptotic protein) blocked this
effect. Induction of apoptosis was also found
for breast, lung, and colon cancer cells. (18)

15) Srivastava, Maya D., et al. “Expression and modulation
of progesterone induced blocking factor (PIBF)
and innate immune factors in human leukemia cell
lines by progesterone and mifepristone.” Leukemia &
lymphoma 48.8 (2007): 1610-1617.

18) Jang, Ji Hoon, et al. “RU486, a glucocorticoid receptor
antagonist, induces apoptosis in U937 human
lymphoma cells through reduction in mitochondrial
membrane potential and activation of p38 MAPK.”
Oncology reports 30.1 (2013): 506-512.

p 345
Patients with dysfunctional immune
systems have higher incidence of cancer. In
2018, Dr. Mayor studied patient registries of
patients with primary immunodeficiency syndrome,
finding a 10-fold increase in lymphoma
in males. (32)

p 346 The Miracle of CAR T cell Therapy

Immunotherapy research reached its crowning
achievement with the introduction of CAR
T cell therapy for CD19+ B-cell hematologic
malignancies (leukemias and lymphomas).
(Note: CAR T cell = Chimeric Antigen Receptor
T Cell).

p 349

Overcoming Cancer Cell Immune
Evasion—Complete Remission of
Lymphoma with Cimetidine

1) Strauchen, James A., et al. “Spontaneous regression
of gastric lymphoma.” Cancer 60.8 (1987): 1872-1875.

2) Ankerst, Jaro, et al. “Complete remission in a patient
with acute myelogenous leukemia treated with leukocyte
α-interferon and cimetidine.” Cancer Immunology,
Immunotherapy 17.1 (1984): 69-71.

p 351
In 1981, Dr. Gifford studied cimetidine in
a mouse lymphoma xenograft model, finding
an improved survival rate (56%) for cimetidine-
treated mice, compared to controls (10%)
at 30 days. (13–14)

p 352

IL-12/IL-18 Preactivated Donor NK cells
In 2018, Dr. Yuan Song et al. studied IL-12/
IL-18 preactivated donor NK cells in a murine
model of B-cell lymphoma, finding enhancement
of the graft vs. lymphoma effect. Note:
graft vs. lymphoma effect is a term used for
the anti-lymphoma immune response of transplanted
bone marrow stem cells. Dr. Song et al.
found:

IL‐12/18 preactivated NK cells mediated
stronger GVL [Graft vs. Lymphoma] effect
than control NK cells mainly due to their
elevated activation/cytotoxicity and sustained
proliferative potential. The IL‐12/18
preactivated NK cells mitigate aGVHD
[Acute Graft vs. Host Disease] despite the
severity of the disease. IL‐12/18‐preactivated
donor NK-cell infusion may be an
effective and safe adoptive therapy after
allo‐HSCT [Allogeneic Hematopoietic Stem
Cell Transplant]. (22)

17) Robertson, Michael J., et al. “A dose-escalation
study of recombinant human interleukin-18 in combination
with rituximab in patients with non-Hodgkin’s
lymphoma.” Journal of immunotherapy 36.6 (2013):
331.

22) Song, Yuan, et al. “IL‐12/IL‐18‐preactivated donor
NK cells enhance GVL effects and mitigate GvHD after
allogeneic hematopoietic stem cell transplantation.”
European journal of immunology 48.4 (2018): 670-682.

p 360
AHCC Enhances Tumor Immune Surveillance

In 2006, Dr. Yunfei Gao studied AHCC (alpha
and beta glucans) in a mouse xenograft model
of melanoma and lymphoma, finding delayed
tumor development associated with activation
of increased anti-tumor immune cells, CD4
and CD8 T Cells, and natural killer (NK cells,
writing:

33) Gao, Yunfei, et al. “Active hexose correlated compound
enhances tumor surveillance through regulating
both innate and adaptive immune responses.”
Cancer Immunology, Immunotherapy 55.10 (2006):
1258-1266.

p 371
Stress-Induced Model of Lymphoma—
Thyroid Hormone Protective

If thyroid hormone enhances our immune
system and protects us from infectious disease,
one might predict thyroid hormone confers
a similar protection from cancer, restoring
immune surveillance.

p 405

Autophagy Inhibitor Combination
in Lymphoma Model

In 2007, Dr. Ravi Amaravadi et al. studied a
c-Myc-induced model of lymphoma in genetically
modified mice. Note: c-Myc is an oncogene
(see the Glossary). This type of lymphoma
lacks a nuclear P53 gene, which makes it resistant
to apoptosis. The lymphoma cells were
genetically modified to give them back a P53
gene, which had been re-engineered to activate
when a drug, tamoxifen, is administered to the
mice. As expected, the c-Myc lymphoma cells
resisted treatment with cytotoxic chemotherapy
in these mice. However, when the P53 gene
in the lymphoma was activated by the administration
of tamoxifen, the lymphoma promptly
regressed for a short time but then recurred
because of induction of “protective autophagy.”
Addition of autophagy inhibition

(i.e., by adding
chloroquine) enhanced the ability of either
P53 or the chemotherapy drug to induce lymphoma
cell death (apoptosis) and prolong the
remission. Dr. Amaravadi and colleagues write:
Activation of p53 was associated with the
rapid appearance of apoptotic cells [dead
cancer cells] and the induction of autophagy
in surviving cells. Inhibition of autophagy
with either chloroquine or ATG5 shRNA
[short hairpin RNA] enhanced the ability
of either p53 activation or alkylating drug
therapy to induce tumor cell death. These
studies provide evidence that autophagy
serves as a survival pathway in tumor cells
treated with apoptosis activators and a
rationale for the use of autophagy inhibitors
such as chloroquine in combination
with therapies designed to induce apoptosis
in human cancers. (37)

37) Amaravadi, Ravi K., et al. “Autophagy inhibition
enhances therapy-induced apoptosis in a Myc-induced
model of lymphoma.” The Journal of clinical investigation
117.2 (2007): 326-336.

40) Djavaheri-Mergny, Mojgan, et al. “Therapeutic
modulation of autophagy in leukaemia and lymphoma.”
Cells 8.2 (2019): 103.

41) Rosich, Laia, et al. “Counteracting autophagy
overcomes resistance to everolimus in mantle cell
lymphoma.” Clinical cancer research 18.19 (2012):
5278-5289

p 406

In 2008, Dr. Kirsteen Maclean et al. studied a
transgenic mouse model of human Burkitt lymphoma,
finding that intermittent chloroquine
treatment activates P53 dependent cell death,
thus preventing development of lymphoma.
This suggests intermittent autophagy inhibition
could be used as part of a maintenance
program to prevent recurrence or relapse of
cancer. Dr. Maclean’s group writes:
Thus chloroquine

Thus chloroquine induces lysosomal stress
and provokes a p53-dependent cell death
that does not require caspase-mediated
apoptosis. These findings specifically
demonstrate that intermittent chloroquine
use effectively prevents cancer in mouse
models of 2 genetically distinct human
cancer syndromes, Burkitt lymphoma
and ataxia telangiectasia, suggesting
that agents targeting lysosome-mediated
degradation may be effective in cancer
prevention. (87)

87) Maclean, Kirsteen H., et al. “Targeting lysosomal
degradation induces p53-dependent cell death and
prevents cancer in mouse models of lymphomagenesis.”
The Journal of clinical investigation 118.1 (2008):
79-88.

p 406

Inhibiting Autophagy and Hedgehog in B-cell Lymphoma

In 2016, Dr. Jiajun Fan et al. studied B-cell
lymphoma in vitro (B-NHL Raji cells) finding
that treatment with vismodegib, an inhibitor
of the Hedgehog signaling pathway, induced
apoptosis and stimulated “protective autophagy.”
Simultaneous treatment with an autophagy
inhibitor was synergistic. (38–40)

38) Fan, Jiajun, et al. “A novel therapeutic approach
against B-cell non-Hodgkin’s lymphoma through co-inhibition
of Hedgehog signaling pathway and autophagy.”
Tumor Biology 37.6 (2016): 7305-7314.

39) Zeng, Xian, and Dianwen Ju. “Hedgehog signaling
pathway and autophagy in cancer.” International journal
of molecular sciences 19.8 (2018): 2279.

40) Djavaheri-Mergny, Mojgan, et al. “Therapeutic
modulation of autophagy in leukaemia and lymphoma.”
Cells 8.2 (2019): 103.

41) Rosich, Laia, et al. “Counteracting autophagy
overcomes resistance to everolimus in mantle cell
lymphoma.” Clinical cancer research 18.19 (2012):
5278-5289.

p 406

In 2012, Dr. Laia Rosich et al. studied the
mTOR inhibitor everolimus in vitro with a
B-cell lymphoma line (mantle cell lymphoma),
a cell type with activated the mTOR pathway.
Resistant lymphoma cells showed a high level
of autophagy.

Accordingly, selective triple knockdown
of the autophagy genes ATG7, ATG5
and ATG3, and pretreatment with the
autophagy inhibitor hydroxychloroquine,
efficiently overcame the resistance to Akt/
mTOR inhibitors, leading to the activation
of the mitochondrial apoptotic pathway….
These results suggest that autophagy
induction protects MCL cells from Akt/
mTOR targeting and counteracting autophagy
may represent an attractive strategy
for sensitizing MCL cells to everolimus-
based therapy. (41)

41) Rosich, Laia, et al. “Counteracting autophagy
overcomes resistance to everolimus in mantle cell
lymphoma.” Clinical cancer research 18.19 (2012):
5278-5289.

Taken together, these results show that the addition of an
autophagy inhibitor (HCQ) overcomes the resistance of MCL cells
to Akt/mTOR inhibitors, leading to efficient apoptosis
induction and suggesting a prosurvival role of autophagy

vitamin D

25) Han, Jing, et al. “Antitumor effects and mechanisms
of 1, 25 (OH) 2D3 in the Pfeiffer diffuse large B
lymphoma cell line.” Molecular medicine reports 20.6
(2019): 5064-5074.

p 419 PPIs for B-Cell Lymphoma

In 2007, Dr. Angelo Yanxiang studied PPI
treatment in a pre-B acute lymphoblastic leukemia
cell line finding use of PPI drug increased
sensitivity to the chemotherapy agent, vinblastine.
Next, the cells showed typical changes in
the lysosomes with increased pH and rupture
of lysosomal membranes. This was followed
by induction of mitochondrial apoptosis.

p 423

Animal studies show PPI treatment reverses
chemoresistance in refractory tumors such as
lymphoma, melanoma, and squamous carcinoma,
and increases efficacy of chemotherapy.
Dr. Iessi and colleague writes:

All these studies provided the first clinical
evidence that PPIs pretreatment could be
easily included into the standard protocols
in clinical oncology with a clear benefit for
patients having the less favorable prognostic
factors. Indeed, pretreatment with
PPIs, by inhibiting proton pumps, induced a
decrease of the protonation of extracellular
tumor environment, in turn allowing the
chemotherapeutics to be fully effective,
improving the effectiveness of either chemical
and biological drugs against cancer.
Thus, tumor alkalinization could improve
the outcome of patients by counteracting
tumor chemoresistance. (54–55)

54) Iessi, Elisabetta, et al. “Rethinking the combination
of proton exchanger inhibitors in cancer therapy.”
Metabolites 8.1 (2018): 2.

55) Papagerakis, Silvana, et al. “Proton pump inhibitors
and histamine 2 blockers are associated with improved
overall survival in patients with head and neck squamous
carcinoma.” Cancer Prevention Research 7.12
(2014): 1258-1269.

p 426
In agreement with these conclusions was a
2019 study by Dr. Chanas LaRue using antihistamines
combined with ibrutinib (a tyrosine
kinase inhibitor) to induce synergistic cancer
cell death in B-Cell lymphoma and leukemia.
(61)

p 428 Clarithromycin

5) Schafranek, Lisa, et al. “Clarithromycin enhances
dasatinib-induced cell death in chronic myeloid leukemia
cells, by inhibition of late stage autophagy.”
Leukemia & lymphoma 54.1 (2013): 198-201.

6) Carella, Angelo Michele, et al. “Clarithromycin
potentiates tyrosine kinase inhibitor treatment in
patients with resistant chronic myeloid leukemia.”
Leukemia & lymphoma 53.7 (2012): 1409-1411.

7) Carella, A. M., et al. “Inhibition of autophagy with
clarithromycin: a new strategy to enhance sensitivity
of CML stem cells to tyrosine kinase inhibitors.”
Leukemia supplements 1.2 (2012): S49-S50.

8) Altman, Jessica K., and Leonidas C. Platanias. “A new
purpose for an old drug: inhibiting autophagy with
clarithromycin.” Leukemia & lymphoma 53.7 (2012):
1255.

p 433
Thymoquinone Potent Anti-Inflammatory Agent- Blocks NF-kB Activation

Thymoquinone has potent anti-inflammatory
effects by preventing activation of nuclear
factor kappa B (NF-kB), the master controller of
inflammation. Studies in cholangiocarcinoma,
B-cell lymphoma, and colon cancer show inactivation
inactivation
of the NF-kB pathway with induction
of apoptosis. Anti-inflammatory effects include
attenuation of cis-platinum chemotherapy toxicity,
protection from testicular and hepatic
injury from diabetes, lead, cadmium and methotrexate
chemotherapy. Protective anti-inflammatory
effects were found in rheumatoid
arthritis and osteoarthritis. (8–10)(87–98)
Thymoquinone has antiviral and antimicrobial
effects. (99–103)

In 2017, Dr. Belkis Atasever Arslan et al.
studied TQ in a lymphoma cell line, finding
induction of P53 mediated apoptosis. (34)

34) Arslan, Belkis Atasever, et al. “Apoptotic effect
of Nigella sativa on human lymphoma U937 cells.”
Pharmacognosy magazine 13.Suppl 3 (2017): S628.

10) Hussain, Azhar R., et al. “Phosphorylated IκBα predicts
poor prognosis in activated B-cell lymphoma and
its inhibition with thymoquinone induces apoptosis via
ROS release.” PloS one 8.3 (2013).

87) Hussain, Azhar R., et al. “Thymoquinone-mediated
suppression of NF-αB activity causes inhibition of cell
viability and induces apoptosis in activated B-cell
sub-type of diffuse large B-cell lymphoma.” (2012):
170-170.

Clarithromycin

In vitro animal xenograft studies and human
studies using CAM have shown efficacy in multiple
myeloma, lymphoma, chronic myeloid leukemia
(CML), and lung cancer. (9)

p 448) CAM for MALT Lymphoma-Human Study – H.Pylori

Clarithromycin is an exemplary model of a
repurposing drug for lymphoma patients; a
long-lasting treatment with a daily dose of
1 g is safe, active and cost-effective … (13)

p 448) Another MALT Lymphoma type occurs in
the eye, in the orbital lymphoid tissue. In this
sub-type, infection with the chlamydia organism
has been implicated, and clarithromycin
induces complete remission as a first-line
treatment. (15)

P 448
Association of Mantle Cell Lymphoma
with H. Pylori Infection

In 2000, Dr. T. G. Paglieroni et al. reported
an association of Helicobacter pylori infection
with mantle cell lymphoma. Dr. Paglieroni’s
group isolated a patient’s mantle cell lymphoma
cells. Even though they are cancer cells,
they are still B cells and produce antibodies
like other B cells. Dr. Paglieroni et al. found the
lymphoma B cells produced massive amounts
of antibodies against the H. pylori organism,
prompting Dr. Paglieroni to recommend antibiotic
treatment for H. Pylori in all mantle cell
lymphoma patients:
Consideration of antibacterial therapy as
an adjunct to chemotherapy is warranted.
The frequency of the association of H.
pylori infection and MCL merits further
study. (16)

p 449

CAM for B-Cell Lymphoma–In Vitro study

In 2004, Dr. Tadashi Ohara et al. reported
in Anti-Cancer Research that CAM directly
induces apoptosis in B-cell lymphoma cells
derived from mice in vitro. Dr. Ohara’s group
identified downregulation of BCL-2 protein
in the CAM-treated cell cultures. BCL2 is the
anti-apoptotic protein, frequently upregulated
in lymphoma, which “immortalizes” the cancer
cells by preventing programmed cell death
(apoptosis). Downregulating BCL-2 restores
the cancer cells’ ability to undergo apoptosis.
This is immensely important in cancer cell
types with upregulated BCL-2. (17)

More CAM/Lymphoma Case reports
In 2011, Dr. Masashi Ohe from Korea
reported success in four cases of various lymphoma
cell types in which complete remission
was achieved using CAM as monotherapy at a
dosage of 400 mg twice a day, given indefinitely.
(18–21)

p 450 CAM/ Spontaneous Remission of
B-Cell Lymphoma of Oral Cavity

In 2015, Dr. Nobuyuki Kaibuchi et al.
reported the case of an 87-year-old man with
a 3-cm mass in the left side of his oral cavity.
Biopsy revealed B-cell lymphoma. A CAT scan
showed the enhancing mass was found near the
left-lower wisdom tooth. A PET scan showed
localized accumulation of radio-isotope at the
mass in the left mandible. On the same day as
the biopsy, the patient was started on azithromycin,
routinely given to prevent infection at
the biopsy site. Three weeks later, the mass had
undergone “spontaneous remission” and disappeared.
Repeat biopsy of the area was negative.
One might speculate that the azithromycin was
responsible for the “spontaneous remission.”
The patient was followed for 2.5 years with no
recurrence. The authors reported 11 similar
cases of “spontaneous disappearance” of oral
lymphomas published in the medical literature.
(22)

17) Ohara, Tadashi, et al. “Antibiotics directly induce
apoptosis in B cell lymphoma cells derived from BALB/c
mice.” Anticancer research 24.6 (2004): 3723-3730.

18) Ohe, Masashi, and Satoshi Hashino. “A case of
follicular B-cell lymphoma treated using clarithromycin.”
The Korean journal of hematology 46.3 (2011):
203-206.
19) Ohe, Masashi, Satoshi Hashino, and Atsuo Hattori.
“Successful treatment of diffuse large B-cell lymphoma
with clarithromycin and prednisolone.” The Korean
journal of hematology 47.4 (2012): 293-297.
20) Ohe, Masashi, and Satoshi Hashino. “Successful
treatment of angioimmunoblastic T-cell lymphoma
with clarithromycin.” Blood research 51.2 (2016):
139-142.

21) Ohe, Masa
shi, and Satoshi Hashino. “Successful
treatment of recurrent follicular B-cell lymphoma with
clarithromycin, prednisolone, and cyclophosphamide.”
The Korean journal of internal medicine 28.3 (2013):
377

22) Kaibuchi, Nobuyuki, et al. “A case of spontaneous
regression of lymphoma in the mandibular gingiva
after biopsy.” Oral and Maxillofacial Surgery Cases 1.3
(2015): 33-37.
23) Portlock, Carol S., et al. “A Positive Prospective Trial
of Antibiotic Therapy in Advanced Stage, Non-Bulky
Indolent Lymphoma.” Tumor microenvironment and
therapy 2.1 (2015): 14-18.

p 454 Itraconazole for Double Hit Lymphoma

Double-hit lymphoma (DHL), having two
separate harmful mutations upregulating
the c-Myc and BCL pathways, is an extremely
aggressive cell-type refractory to conventional
chemotherapy (usually R+CHOP), and median
survival is less than 1.5 years. An in vitro study
by Dr. Juan Gu et al. in Blood (2016) using three
DHL cell lines with escalating doses of itraconazole
showed a strong anti-cancer synergy with
“targeted” oncology drugs venetoclax, a BCL2
inhibitor; Ibrutinib, and bortezomib. Dr. Gu and
colleagues write:

p 455 Disrupting Hexokinase II from Mitochondrial Membrane
Enhances Chemotherapy

As discussed in chapter 4, on cancer as a
metabolic disease, the key location of hexokinase
II on the voltage-dependent anion channel
(VDAC) pore on the outer mitochondrial membrane
can be targeted as a vulnerable metabolic
weakness in cancer cells. By separating
the hexokinase II from the VDAC, mitochondrial
apoptosis can be restored/induced in the cancer
cell. In Blood (2016), Dr. Gu et al. studied
rituximab-resistant non-Hodgkin’s lymphoma
(NHL) cell lines in vitro and found itraconazole
disrupts hexokinase II from the mitochondria
and enhances the efficacy of chemotherapy
agents. Dr. Gu’s group writes:

The disruption of HKII from mitochondria
following itraconazole exposure may
contribute to lower the mitochondrial
membrane potential and enhance the
chemotherapeutic efficacy. Our finding
highlights itraconazole as a potential
therapeutic agent in the treatment of B-cell
malignancies, and strongly supports clinical
translation of its use. (3)

p 459 Boswellia
5-LOX inhibitors are Wnt Inhibitors
Based on the study by Dr. Jessica Roos
et al., the combination of a COX-2 inhibitor
(Celebrex®) with a 5-LOX inhibitor itraconazole
(or ) might be synergistic, targeting
CSCs through Wnt inhibition. (19–25)
They write:

p 459
5-LOX Overexpressed in MCL Cells 7-Fold

5-LOX inhibitors are a promising therapeutic
strategy for mantle cell lymphoma (MCL).
In his 2009 study, Dr. Robert Boyd et al. found
that aberrant 5-LOX activity is upregulated
7-fold in B-Cell lymphoma compared to normal
lymphocytes:

5-lipoxygenase [5-LOX], a key enzyme in
leukotriene biosynthesis, was associated
with lipid rafts and was upregulated 7-fold
in MCL [B-Cell Lymphoma] compared
with normal B cells…. Inhibitors of 5-LOX
activity induced apoptosis in MCL cell lines
and primary chronic lymphocytic leukemia
cells, indicating an important role for the
leukotriene biosynthetic pathway in MCL
and other B-cell malignancies…. this could
be a promising therapeutic strategy for
MCL and CLL [chronic lymphocytic lymphoma].
(22)

Dr. Yilmad Mahshid et al. found high expression
of 5-LOX in malignant MCL cells. (23)
Note: Fenofibrate is another drug targeting lipid
rafts. See chapter 37 for more on this.

Countering CD40 Activation of B-Cell
Lymphoma with 5-LOX inhibitor
In 2005, Dr. Gudmundur Runarsson
observed that treatment of B-CLL cells (chronic
lymphocytic leukemia) with a 5-LOX inhibitor
drug then inhibited CD-40 activation of the
lymphoma cells. Dr. Runarsson writes that the
5 LOX inhibitor treatment:

counteracted CD40-dependent activation
of these cells by inhibiting CD40-induced
DNA synthesis and CD40-induced expression
of CD23, CD54, and CD150. (24)

Note: 5-LOX inhibition by Boswellia (Frankincense)
is discussed in chapter 17 in this book.

p 460
Caution: Concurrent Use of
Itraconazole with Rituximab

The treatment of lymphoma was revolutionized
in 1997 with FDA approval of rituximab, a
monoclonal antibody targeting the B-cell surface
protein CD20. Commonly given IV in combination
with chemotherapy for lymphoma,
rituximab stabilizes the CD20 protein on lipid
rafts. This has a cytotoxic effect on the B cells,
increasing remission rates and prolonging
patient survival. (28)
However, concurrent use of itraconazole with
rituximab is not recommended. Itraconazole is
a lipid raft agent that counteracts (abrogates)
the effect of rituximab. Dr. Pan Pantziarka et al.

p460
Hedgehog Pathway in Lymphoma
Hedgehog Pathway in Lymphoma
In 2015, Drs. Victoria Campbell and Mhairi
Copland reviewed hedgehog signaling in
CSCs with a focus on NHL (Non Hodgkin’s
Lymphoma). Dr. Campbell found the anti-apoptotic
protein BCL-2 is increased by the active
Hedgehog pathway signaling, while inhibition
of Hh downregulates BCL-2:

Expression of BCL-2 is increased in the presence
of active Hh signaling and downregulated
upon inhibition of the pathway….
Components of the Hh pathway and key
downstream targets [BCL-2 and BCL-XL]
are expressed in a variety of NHL [Non-
Hodgkin’s Lymphoma] cell lines … Burkitt’s
Lymphoma cells underwent apoptosis in
the absence of Hh signaling both in vitro
and in vivo. (32)
GLI proteins

GLI proteins are the downstream effectors
of Hh signaling
p 460

In 2008, Dr. Ganapati Hegde et al. writes that
molecular targeting of the hedgehog-GLI signaling
pathway in MCL improved chemotherapy
drug sensitivity:
[It] increased susceptibility to chemotherapeutic
drug, doxorubicin. Also, downregulation
of GLI decreased cyclin D1 and BCL2
transcript levels … and molecular targeting
of GLI is a potential therapeutic approach
to improve the treatment for MCL. (34)

p 461
Itraconazole Inhibits Hh
Pathway in Gastric Cancer

p 463
Simultaneous Suppression
of BTK and mTOR

Dr. Jiao Li et al. In J Cancer (2018) reported
synergistic enhancement with combination of
an mTOR inhibitor drug along with Bruton’s
tyrosine kinase (BTK) inhibitor in B-cell lymphoma.
Originally approved by the FDA in 2016
as an oral capsule, ibrutinib (Imbruvica®) BTK
inhibitor, targets the B-cell receptor (BCR) signaling
pathway and has revolutionized treatment
of B-cell malignancies. In his 2018 study,
Dr. Li et al. used a more potent tyrosine kinase
inhibitor drug, “a novel irreversible BTK inhibitor,
PLS-123, more potent and selective than
ibrutinib.” (44)

Using in vitro screening, Dr. Li’s group discovered
that the combination of BTK inhibitor
drug and mTOR inhibitor drug (in this case,

p 464
Ibrutinib Resistance Reversed
by mTOR Inhibitor
Although dramatic remissions can be
achieved with ibrutinib in lymphoma patients,
eventually an ibrutinib-resistant cell type
develops, with inevitable relapse.

p 465
Pterostilbene a Natural mTOR Inhibitor

Pterostilbene, a methylated resveratrol
derivative is another mTOR inhibitor. Adding
Pterostilbene, a botanical supplement derived
from grapes and blueberries, might be useful
in this case to overcome ibrutinib resistance.
In 2018, Dr. Yu found that pterostilbene attenuates
progression of mantle cell lymphoma by
targeting the PI3K/Akt/mTOR signaling pathway.
(46)

Ibrutinib Resistance and the
Micro-environment

In 2017, Dr. D. Chiron et al. studied the
micro-environment in mantle cell lymphoma
(MCL) and its effect on resistance to drug treatment
with ibrutinib. Dr. Chiron’s group found
that

Inducing Cell Cycle Progression
with CD40 and Cytokine
Cocktail Co-Culture Model

CD40 is a key protein that activates the
dormant B cells. Once activated, the B cells
are no longer dormant. They rapidly proliferate
and become invasive. Dr. Chiron’s lab cultured
twenty-one mantle cell lymphoma (MCL)
samples and found that cell cycle progression
(proliferation) was induced by CD40L, which
was amplified by a MCL-specific cytokine cocktail
(Ck), such as cytokines IL-6, and IL-10.

Otterdal, Kari, Turid Margrethe Pedersen, and Nils Olav Solum. “Release of soluble CD40 ligand after platelet activation: studies on the solubilization phase.” Thrombosis research 114.3 (2004): 167-177.

2) Gu, Juan J., et al. “Itraconazole, an Oral Antifungal
Drug, Inhibits Tumor Growth and Enhances Therapeutic
Agent Activity in Double Hit Lymphoma.” (2016):
5380-5380.

3) Gu, Juan J., et al. “Itraconazole, an Oral Antifungal
Drug, Is Active in Chemotherapy Resistant B-Cell Non-
Hodgkin Lymphoma and Enhances the Anti-Tumor
Activity of Chemotherapy Agents.” Blood. (2016):
5138-5138.

22) Boyd, Robert S., et al. “Protein profiling of plasma
membranes defines aberrant signaling pathways
in mantle cell lymphoma.” Molecular & Cellular
Proteomics 8.7 (2009): 1501-1515

28) Feugier, Pierre. “A review of rituximab, the first
anti-CD20 monoclonal antibody used in the treatment
of B non-Hodgkin’s lymphomas.” Future oncology 11.9
(2015): 1327-1342.

34) Hegde, Ganapati V., et al. “Targeting of sonic hedgehog-
GLI signaling: a potential strategy to improve
therapy for mantle cell lymphoma.” Molecular cancer
therapeutics 7.6 (2008): 1450-1460.

44) Li, Jiao, et al. “The mTOR kinase inhibitor everolimus
synergistically enhances the anti‐tumor effect of
the Bruton’s tyrosine kinase (BTK) inhibitor PLS‐123
on Mantle Cell lymphoma.” International journal of
cancer 142.1 (2018): 202-213..

46) Yu, Dandan, et al. “Targeting the PI3K/Akt/mTOR
signaling pathway by pterostilbene attenuates mantle
cell lymphoma progression.” Acta biochimica et biophysica
Sinica 50.8 (2018): 782-792.

47) Chiron, D., et al. “Novel Targeted Strategies to
Overcome Microenvironment‐Dependent Resistance
in Mantle Cell Lymphoma.” Hematological Oncology
35 (2017): 258-258.

50) Chiron, David, et al. “Rational targeted therapies
to overcome microenvironment-dependent expansion
of mantle cell lymphoma.” Blood 128.24 (2016):
2808-2818.

51) Le Gouill, Steven, et al. “Ibrutinib Plus
Obinutuzumab and Venetoclax in Relapsed/Refractory
Mantle Cells Lymphoma Patients, Results of the OASIS
Phase I Clinical Trial.” (2018): 4158-4158.

52) Le Gouill, Steven, et al. “Ibrutinib, Venetoclax
Plus Obinutuzumab in Newly Diagnosed Mantle Cell
Lymphoma Patients.” (2019): 1530-1530.

53) Papin, Antonin, Steven Le Gouill, and David Chiron.
“Rationale for targeting tumor cells in their microenvironment
for mantle cell lymphoma treatment.”
Leukemia & lymphoma 59.5 (2018): 1064-1072.

62) Zhang, Han, et al. “Hedgehog inhibitors selectively
target cell migration and adhesion of mantle
cell lymphoma in bone marrow microenvironment.”
Oncotarget 7.12 (2016): 14350.

66) Finnes, Heidi D., et al. “Pharmacovigilance during
ibrutinib therapy for chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL) in routine
clinical practice.” Leukemia & lymphoma 58.6 (2017):
1376-1383.

p 476

Retinoids (ATRA) and Cancer

Retinoid drugs such as Accutane (isotretinoin)
are commonly used to treat acne. Another
retinoid variant, ATRA, is FDA-approved for
leukemia and lymphoma.

p 477

Fenofibrate Inhibits Fatty Acid
Synthetase – Hepatoma Model

B-Cell Lymphoma Model

In 2012, Dr. Aadra Bhatt et al. studied the
metabolism of PEL, primary effusion lymphoma,
a cancer thought to be associated with
Herpes virus infection. Dr. Bhatt’s group concludes
that FASN would be a suitable molecular
target for treating lymphoma:

p 476
Retinoids (ATRA) and Cancer

Retinoid drugs such as Accutane (isotretinoin)
are commonly used to treat acne. Another
retinoid variant, ATRA, is FDA-approved for
leukemia and lymphoma.

p 476
FASN in Mantle Cell Lymphoma

In 2012, Dr. Pascal Gelebart et al. studied
mantle cell lymphoma, finding FASN to be
highly expressed, while benign lymph node
tissue and peripheral blood monocytes were
negative. Blocking FASN with orlistat (Xenical),
resulted in significant apoptosis of MCL cells.

p 478

Fenofibrate for Lymphoma and Myeloma

High-endoplasmic reticulum activity renders
multiple myeloma highly sensitive to
mitochondrial inhibitors such as fenofibrate.
In 2017, Dr. Leonard Schmeel et al. studied various
doses of fenofibrate in vitro using seven
human and two murine myeloma/lymphoma
cell lines. He wrote:

Fenofibrate significantly reduced viability
due to apoptosis induction in all investigated
myeloma and lymphoma cell lines in
a dose-dependent manner. (35–36)

Fenofibrate Effective in
Mantle Cell Lymphoma

In 2010, Dr. Z. Zak et al. studied the effect
of fenofibrate in vitro against mantle cell lymphoma,
a rare type of B-Cell lymphoma, reporting
fenofibrate is an agonist for peroxisome
proliferator-activated receptor-alpha (PPARalpha),
inhibits NF-kB and induces apoptosis
in mantle cell lymphoma cells (in vitro). (37)

p 479
Dr. Zak’s group states

that effective serum levels of fenofibrate can be
achieved at clinically relevant doses up to 400
mg per day, taken with the evening meal, which
is well tolerated without significant adverse
effects. They write:

The half-life of fenofibrate has been
reported to be 20 hours in individuals
with normal renal functions, and the level
of fenofibrate required to achieve IC50
[concentration for 50% cancer cell death]
for MCL [Mantle Cell Lymphoma] is within
the therapeutic range that is used to treat
hyperlipidemia. In light of the excellent
safety, tolerability and affordability of
fenofibrate, there is merit in investigating
the possibility of extending the clinical use
of fenofibrate, either as a sole agent or in
combination with conventional chemotherapy,
in the treatment of MCL. (37–39)

Lymphoma: Fenofibrate
Regulates Lipid Metabolism

In 2013, Dr. Jianfeng Huang et al. further elucidated
the effect of fenofibrate on B-cell lymphoma
in a xenograft mouse model. Dr. Huang’s
group found that B-Cell lymphomas hijack host
lipid metabolism to recruit fatty acids to fuel
rapid growth. They write:

B-cell tumors trigger systemic lipid mobilization
from WAT [White Adipose Tissue]
to the liver and increase VLDL/LDL [Low
Density Lipoprotein Cholesterol] release
from the liver to promote tumor growth.

26) Bhatt, Aadra P., et al. “Dysregulation of fatty acid
synthesis and glycolysis in non-Hodgkin Iymphoma.”
Proceedings of the National Academy of Sciences of
the United States of America (2012): 11818-11823.

27) Gelebart, Pascal, et al. “Blockade of Fatty Acid
Synthase Triggers Significant Apoptosis in Mantle Cell
Lymphoma.” PLoS ONE 7.4 (2012).

35) Schmeel, Leonard Christopher, Frederic Carsten
Schmeel, and Ingo GH Schmidt-Wolf. “In vitro apoptosis
induction by fenofibrate in lymphoma and multiple
myeloma.” Anticancer research 37.7 (2017):
3513-3520.

37) Zak, Z., P. Gelebart, and R. Lai. “Fenofibrate
induces effective apoptosis in mantle cell lymphoma
by inhibiting the TNFα/NF-κB signaling axis.” Leukemia
24.8 (2010): 1476.

40) Huang, Jianfeng, et al. “The PPARa agonist fenofibrate
suppresses B-cell lymphoma in mice by modulating
lipid metabolism.” Biochimica et Biophysica Acta
(BBA)-Molecular and Cell Biology of Lipids 1831.10
(2013): 1555-1565.

32) Höring, Elisabeth, et al. “Dual targeting of MCL1
and NOXA as effective strategy for treatment of mantle
cell lymphoma.” British journal of haematology 177.4
(2017): 557-561.

38) Kluin-Nelemans, H. C., P. M. Kluin, and E. Schuuring.
“Cyclin D1 messenger RNA overexpression as a marker
for mantle cell lymphoma.” Oncogene 10.9 (1995):
1833-1840.

p 487
Targeting COX2 in B-Cell Lymphoma,
Leukemia, Multiple Myeloma

Targeting COX2 in B-Cell Lymphoma,
Leukemia, Multiple Myeloma
The cyclo-oxygenase 2 (COX-2) inflammatory
pathway is frequently overexpressed in
hematologic cancers such as leukemia, lymphoma
and multiple myeloma, associated with
poor prognosis. Inhibition of COX-2 with celecoxib
is enormously useful for hematologic cancers,
as discussed in 2008 by Dr. M. P. Bernard
et al., who wrote:
Malignant B cells, namely chronic lymphocytic
leukemia [CLL], highly express
Cox-2, which confers increased survival.
Conversely, Cox-2 selective inhibitors
increased apoptosis in B-CLL cells, indicating
their potential to act as anti-malignant
tumor therapeutic agents. (25)

25) Bernard, M. P., et al. “Targeting cyclooxygenase-2
in hematological malignancies: rationale and promise.”
Current pharmaceutical design 14.21 (2008):
2051-2060.

In 2008, Dr. Bernard’s group summarized
the anti-cancer effects of Cox2 inhibitors, such
as celecoxib (Celebrex):

1) Inhibition of angiogenesis by reducing
VEGF [Vascular Endothelial Growth
Factor]
2) Reduced invasion by reduction in MMP
[Matrix Metallo-Proteinase]
3) Inhibition of proliferation by reduction in
NF-kB, STAT3, MEK and Cyclins, upregulation
of p27 [tumor suppressor gene].

4) Impaired survival by downregulating
BCL-2 [anti-apoptotic protein], NF-kB,
Glutathione, AKT, increasing reactive
oxygen species (ROS), Caspase activity.
5) Significantly attenuated Glutathione
levels.
6) Enhanced host immune function.
7) Reduced T-Reg Cells [immunosuppressive
cells]. (25)

Attenuates Glutathione Levels

In 2008, Dr. Elizabeth Ryan et al. reported
celecoxib 400 mg per day attenuates glutathione
levels in human malignant B cells, and
reduces chronic lymphocytic leukemia (B-CLL)
proliferation and survival. Glutathione is the
main element of the cancer cell’s antioxidant
system. Reducing glutathione renders the cancer
cell more susceptible to damaging effects
of ROS and oxidative therapies. (33)

33) Ryan, Elizabeth P., et al. “Cyclooxygenase-2 independent
effects of cyclooxygenase-2 inhibitors on
oxidative stress and intracellular glutathione content
in normal and malignant human B-cells.” Cancer
Immunology, Immunotherapy 57.3 (2008): 347-358

p 490
Induction of Apoptosis – Downregulates BCL2

In 2011, Dr. Justine Rudner studied the
mechanism of celecoxib-induced apoptosis in
lymphoma cells, finding celecoxib caused the
depletion of the anti-apoptotic protein Mcl-1,
which was sufficient to induce apoptosis, in
spite of BCL2 overexpression.
Note: Mcl-1 = Myeloid cell leukemia 1 (Mcl-1),
an anti-apoptotic protein. BCL-2 is the main
anti-apoptosis protein.
This means that celecoxib induces apoptosis
in cancer cells independent of high BCL-2
protein levels.

58) Rudner, Justine, et al. “Anti-apoptotic Bcl-2 fails
to form efficient complexes with pro-apoptotic
Bak to protect from Celecoxib-induced apoptosis.”
Biochemical pharmacology 81.1 (2011): 32-42.

p 494
Celecoxib Synergy With CAR T Therapy

CAR T therapy, Chimeric Antigen Receptor-
T Cell, is a new form of immunotherapy
described more completely in chapter 27,
“the Mouse that Killed Cancer”. In 2017, Dr.
Dinh suggested Celecoxib would be synergistic
with CAR T therapy—for example, in B-Cell
Lymphoma to sensitize resistant lymphoma
cells to the apoptotic (lytic) effects of the CAR
T cells. Dr. Dinh writes that in Non-Hodgkin’s
Lymphoma (NHL) patients treated with CAR-T
Cell Therapy, the addition of celecoxib COX-2
inhibition provides augmented efficacy, potentially
improving treatment outcome:

Celecoxib is ….an effective apoptotic

inducer of B cell lymphoma…Recent
modern developments…suggest a promising
role of CD19 CAR T cell therapy in NHL.
However, a subset of tumor cells either
inherently resistant or develop resistance
to CAR-mediated immunotherapy. Based
on the apoptotic gene regulatory effects
of celecoxib, we propose that combination
of CD19 CAR T cell therapy and celecoxib
can potentially improve the treatment
outcome of NHL patients. (92)

Similarly, in 2018, Dr. Torres-Collado also
suggested using celecoxib in combination with
CD-19 CAR T therapy in NHL to overcome apoptosis
resistance. (93)

p 496
Case Report – Celecoxib
Synergy with Lenalidamide

Lenalidamide, a new immunomodulatory
drug derived from thalidomide has shown
impressive results in hematologic cancers. In
2018, Dr. Garcia-Recio reported a 35-year-old
female patient with NHL (non-Hodgkin’s lymphoma)
refractory to six lines of chemotherapy.
Since chemotherapy was no longer useful, the
patient was switched to a combination of lenalidamide
(20 mg/d for 3 of every 4 weeks) and
celecoxib (200 mg orally twice a day) achieving
complete remission for 22 months. This is very
impressive. (101)

101) Garcia-Recio, Marta, et al. “Complete response
associated with lenalidomide and celecoxib in a case of
primary refractory Hodgkin lymphoma.” OncoTargets
and therapy 11 (2018): 6599

33) Ryan, Elizabeth P., et al. “Cyclooxygenase-2 independent
effects of cyclooxygenase-2 inhibitors on
oxidative stress and intracellular glutathione content
in normal and malignant human B-cells.” Cancer
Immunology, Immunotherapy 57.3 (2008): 347-358.

92) Dinh, Tam NM, Alexandra S. Onea, and Ali R.
Jazirehi. “Combination of celecoxib (Celebrex®) and
CD19 CAR-redirected CTL immunotherapy for the
treatment of B-cell non-Hodgkin’s lymphomas.” Am J
Clin Exp Immunol 6.3 (2017): 27-42.

93) Torres-Collado, Antoni, and Ali Jazirehi.
“Overcoming resistance of human non-Hodgkin’s lymphoma
to CD19-CAR CTL therapy by celecoxib and histone
deacetylase inhibitors.” Cancers 10.6 (2018): 200.

123) Wun, Theodore, Hayes McKnight, and Joseph
Tuscano. “Increased cyclooxygenase-2 (COX-2): A
potential role in the pathogenesis of lymphoma.”
Leukemia Research 28.2 (2004): 179-190.

141) Gallouet, Anne-Sophie, et al. “COX-2–Independent
Effects of Celecoxib Sensitize Lymphoma B Cells to
TRAIL-Mediated Apoptosis.” Clinical Cancer Research
20.10 (2014): 2663-2673.

142) Phipps, Richard P., Elizabeth Ryan, and Steven H.
Bernstein. “Inhibition of cyclooxygenase-2: a new targeted
therapy for B-cell lymphoma?” (2004): 109-111.

112) Wang, Weijun, et al. “Efficacy of celecoxib in
the treatment of CNS lymphomas: an in vivo model.”
Neurosurgical focus 21.5 (2006): 1-8.

45) Shi, W. Y., et al. “Therapeutic metformin/AMPK
activation blocked lymphoma cell growth via inhibition
of mTOR pathway and induction of autophagy.” Cell
death & disease 3.3 (2012): e275-e275.

500
49) Granato, Marisa, et al. “Quercetin induces apoptosis
and autophagy in primary effusion lymphoma
cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling
pathways.” The Journal of nutritional biochemistry 41
(2017): 124-136.

60) Johnson, Amy J., et al. “A novel celecoxib derivative,
OSU03012, induces cytotoxicity in primary CLL
cells and transformed B-cell lymphoma cell line via a
caspase-and Bcl-2–independent mechanism.” Blood
105.6 (2005): 2504-2509.

p 508

Diclofenac for Lymphoma Induces
Apoptosis via P73 and P53

We have previously discussed the P53 gene,
frequently dysregulated in cancer cells, as the
“Guardian of the Genome.” Another under-appreciated
member of the P53 family is the P73
gene, which is highly conserved and rarely
mutated in cancers. In this case, the ratio of two
P73 isoforms determines apoptosis independent
of P53. By increasing the Tap73 isoform,
apoptosis can be induced.

In 2015 and 2016, Dr. Hassan did a number
of studies on the modulation of p73 isoform
expression in B-Cell Lymphoma (mantle cell
MCL) model, finding:

Diclofenac induced a concentration and
duration dependent increase in Tap73
[apoptosis isoform] , cell cycle arrest,
cell death, and inhibited MCL cell growth
independent of p53 status … Diclofenac
treatment was associated with increased
activity of caspases 3, 7, and 8 [mitochondrial
apoptosis] and induction of p53
transcriptional target genes. These studies
demonstrate the potential for diclofenac
as novel therapeutic agent in MCL independent
of p53 status. (16–23)

Similar to diclofenac, celecoxib also upregulates
the pro-apoptotic isoform, Tap73. The
two COX2 inhibitor drugs also attenuate Wnt/
Beta-Catenin signaling, a CSC pathway. (24–25)

16) Hassan, Hesham M., et al. “Modulation of p73
isoforms expression induces anti-proliferative and
pro-apoptotic activity in mantle cell lymphoma independent
of p53 status.” Leukemia & lymphoma 57.12
(2016): 2874-2889.

17) Hassan, Hesham M., et al. “The COX inhibitor,
diclofenac induces mantle cell lymphoma apoptosis
independent of p53 status.” (2015): 2632-2632.

18) Hassan, Hesham, et al. “Diclofenac Induces
Apoptosis and Suppresses Diffuse Large B-Cell
Lymphoma Proliferation Independent of P53 Status.”
(2014): 5485-5485

19) Hassan, H. M., Bhavana J. Dave, and Rakesh K.
Singh. “TP73, an under-appreciated player in non-Hodgkin
lymphoma pathogenesis and management.”
Current molecular medicine 14.4 (2014): 432-439.

p 537
Platelet-Derived Growth Factor
(PDGF) and Angiogenesis

Cancer cells use PDGF to induce new vessel
formation, a process called angiogenesis.
Blocking receptors for PDGF in pericytes
(cells lining the blood vessels) results in loss
of neovascular growth needed to sustain tumor
growth in lymphoma. A new oncology drug
called Gleevec® (imatinib), FDA-approved
for treatment of chronic lymphocytic leukemia
(CLL) is a blocker of PDGF receptors and
a potent angiogenesis inhibitor in a lymphoma
xenograft animal model. (18–19)

Blocking Platelet-Derived
Growth Factor with Gleevec

In 2012, Dr. Daniela Laimer et al. studied
anaplastic large cell lymphoma in transgenic
mice and in a human case report, finding a
dramatic response to blocking PDGF receptors
(PDGFR) with imatinib, with rapid, sustained
remission:
Therapeutic inhibition of PDGFRB [with
Gleevec – imatinib], markedly prolonged
survival of NPM-ALK [lymphoma] trans

genic mice and increased the efficacy of an
ALK-specific inhibitor in transplanted NPMALK
tumors. Notably, inhibition of PDGFRA
and PDGFRB in a patient with refractory
late-stage NPM-ALK(+) ALCL resulted in
rapid, complete and sustained remission.
(20)\

Note: PDGFR = Platelet-Derived Growth Factor
Receptor A and B. NPM-ALK is a specific chromosomal
translocation which produces lymphoma

Dipyridamole Decreases
Platelet Release of PDGF

According to Dr. Takehara, who studied the
effect of dipyridamole on platelets in 1987 and
1990:
Dipyridamole specifically decreases platelet-
derived growth factor [PDGF] release
from platelets….and decrease its serum
concentration. (21–22)

p 519
Nine-Fold Upregulated
Phosphodiesterase in Lymphoma

In 2011, Dr. Lingzhi Zhang et al. studied 85
patients with CLL and compared them to 35
normal controls, finding greater than 9-fold
elevation in phosphodiesterase 7B messenger
RNA (PDE7B mRNA) expression in the top
quartile of CLL patients, which predicted more
aggressive disease with shorter time to treatment
(36 months vs. 77 months). (39)

In 2013, Dr. Cheng Fang et al. found higher
expression of phosphodiesterase messenger
RNA (PDE7B), indicating poor prognosis in
B-cell lymphoma. (40)

In 2016, Drs. Jeffrey Ricardo and Aguiar
Cooney studied phosphodiesterase (PDE4
type 4) inhibitors in B-cell lymphoma, finding
that PDE4 inhibition downregulates the B-cell
receptor related kinase (similar to the kinase
inhibitor drug ibrutinib), the PI-3K pathway,
and VEGF, inducing apoptosis and blocking
angiogenesis. In lymphoma cells, cAMP is inhibitory.
PDE abrogates this effect by converting
cAMP to inactive AMP, allowing higher PI3K/
AKT-driven VEGF expression in the lymphoma
cell. Thus, PDE inhibition with dipyridamole
increases Cyclic AMP inside the lymphoma cell,
which induces cell death. (41–47)

39) Zhang, Lingzhi, et al. “Cyclic nucleotide phosphodiesterase
7B mRNA: An unfavorable characteristic in
chronic lymphocytic leukemia.” International Journal
Of Cancer 129.5 (2011): 1162-1169.

40) Fang, Cheng, et al. “High expression of cyclic nucleotide
phosphodiesterase 7B mRNA predicts poor prognosis
in mantle cell lymphoma.” Leukemia research
37.5 (2013): 536-540.

41) Cooney, Jeffrey D., and Ricardo CT Aguiar.
“Phosphodiesterase 4 inhibitors have wide-ranging
activity in B-cell malignancies.” Blood, The Journal of
the American Society of Hematology 128.25 (2016):
2886-2890.

42) Suhasini, Avvaru N., et al. “A phosphodiesterase
4B-dependent interplay between tumor cells and the
microenvironment regulates angiogenesis in B-cell
lymphoma.” Leukemia 30.3 (2016): 617-626.

43) Murray, F., and P. A. Insel. “Targeting cAMP in
chronic lymphocytic leukemia: a pathway-dependent
approach for the treatment of leukemia and lymphoma.”
Expert opinion on therapeutic targets 17.8
(2013): 937.

44) Suhasini, Avvaru N., et al. “A phosphodiesterase
4B-dependent interplay between tumor cells and the
microenvironment regulates angiogenesis in B-cell
lymphoma.” Leukemia 30.3 (2016): 617-626.

45) Coffino, Philip, Henry R. Bourne, and G. M. Tomkins.
“Mechanism of lymphoma cell death induced by cyclic
AMP.” The American journal of pathology 81.1 (1975):
199.

46) Nam, Jehyun, et al. “Disruption of the Myc-PDE4B
regulatory circuitry impairs B-cell lymphoma survival.”
Leukemia 33.12 (2019): 2912-2923.

47) Kelly, Kevin, et al. “Safety and pharmacodynamics
of the PDE4 inhibitor roflumilast in advanced B-cell
malignancies.” Clinical Cancer Research 23.5 (2017):
1186-1192.

p 520

Dipyridamole with Chemotherapy
In 2010, Dr. Y. J. Jiang et al. observed that DP
is beneficial in lymphoma patients by preventing
platelet activation during chemotherapy. Dr.
Jiang and colleagues write:
It is concluded that the patients with malignant
lymphoma usually accompany with
platelet activation and hyperfibrinogenemia
in peripheral blood. Applying dipyridamole
routine dosage in chemotherapy can
efficiently restrain platelet activation. (51)

p 523

Preclinical Studies (in vitro and in vivo xenografts)
show statin drugs effective in the following
cancer cell lines:
• Lymphoma (117–118)

117) Qi, X. F., et al. “HMG-CoA reductase inhibitors
induce apoptosis of lymphoma cells by promoting ROS
generation and regulating Akt, Erk and p38 signals via
suppression of mevalonate pathway.” Cell death & disease
4.2 (2013): e518.

118) van de Donk, Niels WCJ, et al. “Protein geranylgeranylation
is critical for the regulation of survival and
proliferation of lymphoma tumor cells.” Clinical cancer
research 9.15 (2003): 5735-5748.

p 525

In patients receiving treatment with rituximab
given IV for lymphoma, statins will interfere
with efficacy of the drug. Concomitant use
of statins with rituximab is not recommended.
Similarly, another drug mentioned in this book,
itraconazole, should not be used with rituximab,
as recruitment of the CD20 marker is
inhibited. (142–143)

p 526

12) Cesca, Christine, Jonathan Ben-Ezra, and Roger S.
Riley. “Platelet satellitism as presenting finding in mantle
cell lymphoma: a case report.” American journal of
clinical pathology 115.4 (2001): 567-570.

13) Gatignol, Anne, et al. “B-cell non-Hodgkin lymphoma
discovery after observation of a platelet
satellitism around atypical lymphocytes.” Annales de
biologie clinique. Vol. 77. No. 2. 2019

18) Ruan, Jia, et al. “Imatinib disrupts lymphoma
angiogenesis by targeting vascular pericytes.” Blood
121.26 (2013): 5192-5202.

19) Chute, John P., and Heather A. Himburg. “Imatinib
tackles lymphoma via the PDGFRβ+ pericyte.” Blood
121.26 (2013): 5107-5108.

20) Laimer, Daniela, et al. “PDGFR blockade is a rational
and effective therapy for NPM-ALK–driven lymphomas.”
Nature medicine 18.11 (2012): 1699.

40) Fang, Cheng, et al. “High expression of cyclic nucleotide
phosphodiesterase 7B mRNA predicts poor prognosis
in mantle cell lymphoma.” Leukemia research
37.5 (2013): 536-540.

42) Suhasini, Avvaru N., et al. “A phosphodiesterase
4B-dependent interplay between tumor cells and the
microenvironment regulates angiogenesis in B-cell
lymphoma.” Leukemia 30.3 (2016): 617-626.

43) Murray, F., and P. A. Insel. “Targeting cAMP in
chronic lymphocytic leukemia: a pathway-dependent
approach for the treatment of leukemia and lymphoma.”
Expert opinion on therapeutic targets 17.8
(2013): 937.
44) Suhasini, Avvaru N., et al. “A phosphodiesterase
4B-dependent interplay between tumor cells and the
microenvironment regulates angiogenesis in B-cell
lymphoma.” Leukemia 30.3 (2016): 617-626.
45) Coffino, Philip, Henry R. Bourne, and G. M. Tomkins.
“Mechanism of lymphoma cell death induced by cyclic
AMP.” The American journal of pathology 81.1 (1975):
199.
46) Nam, Jehyun, et al. “Disruption of the Myc-PDE4B
regulatory circuitry impairs B-cell lymphoma survival.”
Leukemia 33.12 (2019): 2912-2923.

51) Jiang, Y. J., et al. “Influence of dipyridamole on
expression of PAC-1 and CD62p in patients with malignant
lymphoma.” Zhongguo shi yan xue ye xue za zhi
18.4 (2010): 923-926.

52) Hirose, M., et al. “Synergistic inhibitory effects of
dipyridamole and vincristine on the growth of human
leukaemia and lymphoma cell lines.” British journal of
cancer 56.4 (1987): 413-417.

117) Qi, X. F., et al. “HMG-CoA reductase inhibitors
induce apoptosis of lymphoma cells by promoting ROS
generation and regulating Akt, Erk and p38 signals via
suppression of mevalonate pathway.” Cell death & disease
4.2 (2013): e518.

118) van de Donk, Niels WCJ, et al. “Protein geranylgeranylation
is critical for the regulation of survival and
proliferation of lymphoma tumor cells.” Clinical cancer
research 9.15 (2003): 5735-5748.

143) Ringshausen, Ingo, et al. “Antifungal therapy
with itraconazole impairs the anti-lymphoma effects
of rituximab by inhibiting recruitment of CD20 to cell
surface lipid rafts.” Cancer research 70.11 (2010):
4292-4296.

p 535 tocotrienol Vitamin E

Leukemia/Lymphoma (5-6) (44-50)

5) Ghanem, Paola, et al. “The Vitamin E Derivative
Gamma Tocotrienol Promotes Anti-Tumor Effects in
Acute Myeloid Leukemia Cell Lines.” Nutrients 11.11
(2019): 2808.

6) Ng, K. L., A. K. Radhakrishnan, and K. R. Selvaduray.
“Gamma-Tocotrienol Inhibits Proliferation of Human
Chronic Myeloid Leukemic Cells via Activation of
Extrinsic and Intrinsic Apoptotic Pathways.” J. Blood
Disord. Ther 1640 (2016): 1-11.

44) Ladikou, Eleni-Eirini, and Eva Kassi. “The emerging
role of estrogen in B cell malignancies.” Leukemia &
Lymphoma 58.3 (2017): 528-539.

45) Yakimchuk, Konstantin, et al. “Inhibition of lymphoma
vascularization and dissemination by estrogen
receptor β agonists.” Blood, The Journal of the
American Society of Hematology 123.13 (2014):
2054-2061.

46) Roemer, Klaus, and Michael Pfreundschuh. “How
do estrogens control lymphoma?.” Blood, The Journal
of the American Society of Hematology 123.13 (2014):
1980-1981.

p 537

Alternatively blocking estrogen with an
aromatase inhibitor drug stimulated B Cell
Lymphoma growth in a mouse xenograft model
by Dr. Talaber in 2016, “highlighting a protective
role for estrogens in lymphoma pathogenesis”.
(47-50)

47) Talaber, Gergely, et al. “Inhibition of estrogen
biosynthesis enhances lymphoma growth in mice.”
Oncotarget 7.15 (2016): 20718.

48) Rota, Sarah-Grace, et al. “Estrogen receptor β is
a novel target in acute myeloid leukemia.” Molecular
Cancer Therapeutics 16.11 (2017): 2618-2626.

49) Ladikou, Eleni-Eirini, and Eva Kassi. “The emerging
role of estrogen in B cell malignancies.” Leukemia &
Lymphoma 58.3 (2017): 528-539.

50) Rudelius, Martina, et al. “The G protein-coupled
estrogen receptor 1 (GPER-1) contributes to the proliferation
and survival of mantle cell lymphoma cells.”
haematologica 100.11 (2015): e458

p 553
ATRA (All Trans Retinoic Acid – Vesinoid®)

Is a retinoid, a synthetic version of vitamin A, FDA
approved for treatment of lymphoma and leukemia,
and actually “curative” for promyelocytic
leukemia. ATRA regulates miRNA and augments
anti-tumor immunity by reducing the population of
MDSC’s (Myeloid Derived Suppressor Cells). This
improves efficacy of CAR-T therapy and anti-angiogenesis
therapy. Retinoids (Vitamin A derivatives)
are synergistic with the PPAR agonist drugs such
as Fenofibrate, improving anti-cancer efficacy.
The anti-acne drug, Accutane® (isotretinoin) and
many other Vitamin A derivatives (retinoids) are
repurposed as anti-cancer drugs. (19-23)

p 554

Auranofin (AF)
Is an old gold-containing, FDA approved, rheumatology
drug used for arthritis, repurposed as
anticancer drug via inhibition of the thioredoxin
reductase anti-oxidant system (TrxR) , thus sensitizing
cancer cells to oxidative therapies. Auranofin
(AF) inhibits the PI3K/AKT/mTOR pathway and has
been repurposed for treatment of P53 mutated
and PTEN-deleted refractory B Cell Lymphoma,
and enhances activity of Ibrutinib in EGFR mutant
Lung Cancer. Auranofin has potent preclinical
activity in CLL (chronic lymphocytic leukemia).
Auranofin was found surprisingly effective against
B Cell lymphoma (Mantle Cell) mouse xenografts,
overcoming drug resistance in the stromal microenvironment.
Apparently, TrxR is upregulated in
lymphoma located in the stromal microenvironment,
where AF transforms the TrxR system into
an ROS generating anti-cancer weapon. However,
the main AF anticancer mechanism of action
(MOA) is independent of the TrxR system, found
to be dual GLYCOLYSIS and OXPHOS inhibition
with suppression of ETC Complex II activity, and
inhibition of GAPDH (glyceraldehyde phosphate
dehydrogenase), a key Glycolytic enzyme, with
reduction in cellular ATP. Normal cells were able
to compensate and were unaffected. Recent
studies show triple combination of AF, Vitamin C
(ascorbate) and Vitamin K (Menadione) synergistic
against TNBC (triple negative breast cancer) in
vitro and in vivo. Similarly, the combination of
Auranofin and anti-PD-L1 checkpoint inhibitor drug
is synergistically effective for TNBC. Auranofin has
antiviral activity, inhibits corona virus replication
(SARS-COV-2), as well as anti-inflammatory and
antibacterial effects against MERSA and Clostridia.
(24-31)

p 555 BH3 Mimetic

is B-cell lymphoma 2 (Bcl-2) Homology 3 mimetic,
a small orally available molecule (Venetoclax®)
which inhibits the anti-apoptotic Bcl-2 protein family,
including Bcl-2, Bcl-xl and Bcl-w. Thus restoring
apoptosis in cancer cells.

p 556

Cancer as a Parasitic Disease
This is the theory that cancer resembles a parasitic
disease, supported by animal models in which
parasitic diseases closely resemble lymphoma and
other cancers. This theory is also supported by the
sheer fact that many anti-parasitic and anti-fungal
drugs are effective repurposed anti-cancer drugs.
(40)

p 557

CD40 activation

Located at the cell surface membrane, CD40 is a
TNF (tumor necrosis factor) receptor expressed
on cell surface of B Cells, T-Cells (immune cells)
and many cancer cell types. B cell malignancies
(lymphoma) are heavily CD-40 dependent for activation,
proliferation and survival. CD-40 activation
is prevented by inhibiting the 5-LOX inflammatory
pathway (with Boswellia and Itraconazole, for
example)

p 557
Cyclin D1

Is an oncogene which regulates cell cycle progression
(cell replication), a target gene for the
Wnt and MAPk pathways. Upregulated Cyclin D1
makes the cells replicate faster, a poor prognostic
feature in cancer. Downregulation of Cyclin D1 is
a valid anti-cancer strategy. Nuclear staining and
detection of Cyclin D1 on immunohistochemistry is
common in Mantle Cell Lymphoma. (72-73)

p 559
FASN (Fatty Acid Synthetase)

Is an enzyme frequently upregulated in cancer
cells (such as hepatoma and B-Cell Lymphoma)
involved in generating fatty acids for tumor energy
requirements. FASN is blocked by Fenofibrate,
Orlistat® and Quercetin. Blocking FASN is a valid
anti-cancer strategy. FASN inhibition also leads to
microtubule disruption and synergizes with other
microtubule drugs such as mebendazole, and taxol
(taxanes).

p 562
Hedgehog Pathway (Hh)
First identified in mutant fruit flies in 1980, the
Hedgehog signaling pathway is a cancer stem
cell pathway. The GLI protein is the downstream
effector. Normally Hh is used for embryonic development,
however upregulation is commonly seen
in cancer cells. In the growing embryo, Hh controls
the differentiation of cells into organs, cell proliferation,
stem cell maintenance, and regulation of
growth factors. Inhibition of Hh causes decrease
in BCL2 and Cyclin D1 in lymphoma, and targets
cancer stem cells.

p 565
MTA1 (Metastasis Associated Protein1)

is an essential downstream effector of the c-Myc
oncoprotein, regulates EMT (epithelial-to-mesenchymal
transition) and metastatic progression.
MTA1 also inhibits p53-induced apoptosis by
deacetylation of p53. MTA1 is widely up-regulated
in many cancer cell types including most lymphomas,
breast, endometrial, colorectal, gastric,
esophageal, pancreatic, ovarian, non–small cell
lung, prostate, and hepatocellular carcinomas.
MTA1 is widely up-regulated in human B-cell lymphomas.
Mice genetically modified to over-express
MTA1 have a very high rate of spontaneous B cell
lymphoma. Pterostilbene Resveratrol, Curcumin
and Diascorea inhibit MTA1, useful in prostate
cancer, chemoprevention and treatment. (182-187)

p 571

TrxR thioredoxin reductase system,
a selenium based intracellular anti-oxidant system
which protects the cancer cells from excess ROS
(reactive oxygen species). TrxR is inhibited by an
old gold containing rheumatology drug, Auranofin,
thus sensitizing cancer cells to oxidative therapies.
(21) Auranofin has been repurposed to treat P53-
mutated or PTEN deficient B cell lymphoma. (172)

24) Wang, Jeffrey, et al. “Repurposing auranofin to
treat TP53-mutated or PTEN-deleted refractory B-cell
lymphoma.” Blood cancer journal 9.12 (2019): 1-6.

28) Yang, Mengqi, et al. “Effective Elimination of
Lymphoma Cells in Stromal Microenvironment by
Double Impact on ROS and ATP Metabolism Using
Auranofin.” (2020).

73) Zukerberg, Lawrence R., et al. “Cyclin D1 expression
in non-Hodgkin’s lymphomas: detection by
immunohistochemistry.” American journal of clinical
pathology 103.6 (1995): 756-760.

113) Mudassar, Muhammad, et al. “Ki-67 Proliferative
Index in The Non-Hodgkin’s Lymphoma and Its Clinical
Significance.” Annals of Punjab Medical College
(APMC) 13.2 (2019): 108-112.

186) Bagheri-Yarmand, Rozita, et al. “Metastasisassociated
protein 1 transgenic mice: a new model
of spontaneous B-cell lymphomas.” Cancer Research
67.15 (2007): 7062-7067.

================================================
since 2020

Iveremctin for leukemiaa 60 mg per day

de Castro Jr, Claudio Galvao, Lauro Jose Gregianin, and Jan A. Burger. “Continuous high-dose ivermectin appears to be safe in patients with acute myelogenous leukemia and could inform clinical repurposing for COVID-19 infection.” Leukemia & Lymphoma 61.10 (2020): 2536-2537.

Liu, Jian, et al. “Progress in understanding the molecular mechanisms underlying the antitumour effects of ivermectin.” Drug design, development and therapy 14 (2020): 285.

Draganov, Dobrin, et al. “Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer.” NPJ breast cancer 7.1 (2021): 1-11.

Mezzatesta, Caterina, et al. “Repurposing anthelmintic agents to eradicate resistant leukemia.” Blood cancer journal 10.6 (2020): 1-11.

Huang, Haoyang, et al. “Progress in Redirecting Antiparasitic Drugs for Cancer Treatment.” Drug Design, Development and Therapy 15 (2021): 2747.

Cho, Yongmin, et al. “Review of Natural Compounds for the Management and Prevention of Lymphoma.” Processes 8.9 (2020): 1164.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8304872/
Berehab, Mimoune, et al. “Apoptotic and Non-Apoptotic Modalities of Thymoquinone-Induced Lymphoma Cell Death: Highlight of the Role of Cytosolic Calcium and Necroptosis.” Cancers 13.14 (2021): 3579.

Zou, Hai, et al. “Silibinin: an old drug for hematological disorders.” Oncotarget 8.51 (2017): 89307.

DCA

Agnoletto, Chiara, et al. “Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3.” Oncotarget 5.12 (2014): 4347.

Dipyridaamole decreasses B cell lymphoma 50%

https://pubmed.ncbi.nlm.nih.gov/34553368/
Huang, Wuqing, et al. “Use of dipyridamole is associated with lower risk of lymphoid neoplasms: a propensity score‐matched cohort study.” British Journal of Haematology (2021).

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.

Gaidano, Valentina, et al. “The synergism between DHODH inhibitors and dipyridamole leads to metabolic lethality in acute myeloid leukemia.” Cancers 13.5 (2021): 1003.

ChemoFit

Dr. Sherry Bradford PhD, Accutheranostics, Amherst NY
ChemoFitTM CS/CR assay from Acccutheranostics in Amherst, NY is one such assay which
uses fresh live tumour cells, uncultured
• ChemoFit TM was performed on a 50 year old

Published on by Jeffrey Dach MD

About Jeffrey Dach MD

Medical Director of TrueMedMD, a Clinic in Davie Florida specializing in Bioidentical Hormones and Natural thyroid. Office address 7450 Griffin Road Suite 190, Davie, Florida 33314 telephone 954-792-4663