Index for Pancreatic Cancer

Index for Pancreatic Cancer

Cracking Cancer Toolkit by Jeffrey Dach MD

Repurposed Drugs for Pancreatic Cancer

p 24. Repurposed Drugs for Pancreatic Cancer

In 2019, Dr. Matthias Ilmer provided an
updated list of repurposed drugs for pancreatic
cancer, including (28):
• Hydroxychloroquine—antimalarial
autophagy inhibitor
• Disulfiram—(Antabuse) for alcohol
addiction
• Itraconazole—antifungal
• Propranolol—beta blocker
• Vitamin D3

p.26 28) Ilmer, Matthias, et al. “Repurposed drugs in pancreatic
ductal adenocarcinoma: An update.” The Cancer Journal 25.2 (2019): 134-138.

p.38
27) Papasotiriou, Ioannis, et al. “Detection of circulating tumor cells in patients with breast, prostate, pancreatic, colon and melanoma cancer: A blinded comparative study using healthy donors.” Journal of Cancer Therapy 6.07 (2015): 543

p 51
Thiamine and R-Alpha Lipoic Acid Analogous to DCA

In 2014, Dr. Bradley Hanberry et al. studied high-dose thiamine in pancreatic cancer and neuroblastoma cell lines in vitro, finding that
the mechanism of reduction in proliferation was similar to that of DCA:

Thiamine exhibited a lower IC50 value in both cell lines compared to DCA. Both thiamine and DCA reduced the extent of
PDH phosphorylation [PDH inactivation], reduced glucose consumption, lactate production, and mitochondrial membrane potential. High-dose thiamine and DCA did not increase ROS but increased caspase-3
activity [apoptosis]…. Our findings suggest that high-dose thiamine reduces cancer cell proliferation by a mechanism similar to that described for dichloroacetate. (33)

Both thiamine and alpha lipoic acid are
co-factors for the PDC complex, standing at
the entry point for pyruvate into the mitochondrial
electron transport chain. Both thiamine
and alpha lipoic acid are routinely recommended
along with DCA, either separately
or all together in a liquid supplement called
Poly-MVA, prominently mentioned by Dr. Paul
Anderson in his (2018) book, Outside the Box
Cancer Therapies.(1) Poly-MVA is a liquid polymer
containing palladium, thiamine, and alpha
lipoic acid. The addition of the rare earth metal,
palladium, serving as electron donor, provides
added synergy.

 

p.56 DCA and Pancreatic Cancer Stem Cells

Drs. Tataranni and Piccoli (2018) studied
DCA in pancreatic cancer cell lines in vitro and
in vivo using a xenograft mouse model and
found downregulation of CSC markers and
inhibition of spheroid formation and viability,
concluding:

The novelty that DCA might affect the
cancer stem cell compartment is therapeutically
relevant. (90)

p. 67
90) Tataranni, Tiziana, et al. “Dichloroacetate Affects
Mitochondrial Function and Stemness-Associated
Properties in Pancreatic Cancer Cell Lines.” Cells 8.5
(2019): 478

 

p.71
Eventually, Jim got sick and stayed in
bed for a week, refusing to go to work. A friend
found him and took Jim to the emergency room,
where the doctor ordered lab tests and a CAT
scan, which showed Jim had pancreatic cancer
with metastatic spread to the liver.

 

p. 71
According to Dr. Corona Kim-Fuchs et al.
(2014), the answer is yes: “Chronic stress
accelerates pancreatic cancer growth and
invasion.”(1) Chronic stress activates the sympathetic
nervous system, which secretes catecholamines,
which feed cancer growth. (1–5)

p 71.
Dr. Steven Cole et al. (2015) write that in
vivo animal models of stress show accelerated
cancer growth, preventable with an old betablocker
drug (propranolol):
Experimental analyses with in vivo animal
models have now shown that behavioral
stress can accelerate the progression of
breast, prostate, and ovarian carcinomas,
neuroblastomas, malignant melanomas,
pancreatic carcinoma, and some haematopoietic
cancers such as leukaemia. In many
of these experimental models, the biological
effects of stress could be efficiently
blocked by βeta-adrenergic antagonists
and mimicked by pharmacologic βeta-agonists.
(4)

p 79

Propranolol Effective for
Cancer Cell Types
Pancreatic cancer (93–95)(1)

 

p 81.
1) Kim-Fuchs, Corina, et al. “Chronic stress accelerates
pancreatic cancer growth and invasion: a critical
role for beta-adrenergic signaling in the pancreatic
microenvironment.” Brain, behavior, and immunity
40 (2014): 40-47.

 

p 82
27) Gonzalez, Nicholas James, and Linda Lee Isaacs.
“Evaluation of pancreatic proteolytic enzyme treatment
of adenocarcinoma of the pancreas, with nutrition
and detoxification support.” Nutrition and cancer
33.2 (1999): 117-124

p. 85

93) Partecke, Lars Ivo, et al. “Chronic stress increases
experimental pancreatic cancer growth, reduces survival
and can be antagonised by beta-adrenergic receptor
blockade.” Pancreatology 16.3 (2016): 423-433.

94) Ilmer, Matthias, et al. “Repurposed drugs in pancreatic
ductal adenocarcinoma: An update.” The
Cancer Journal 25.2 (2019): 134-138.

95) Blair, Alex, et al. “345–Non-Selective β-Adrenergic
Blockade Impacts Pancreatic Cancer Tumor Biology,
Decreases Perineural Invasion and Improves Patient
Survival.” Gastroenterology 156.6 (2019): S-1394.

p 87
A New Discovery: ALA
Effective for Cancer

After finishing his training, Dr. Berkson
embarked on his medical career treating liver
disease with ALA at his clinic in Las Cruces, New
Mexico. There he observed something unexpected
in liver disease patients who also had
cancer. Pancreatic and hepatic cancer patients
went into remission after IV alpha lipoic acid
treatment. (4) The alpha lipoic acid had a beneficial
side effect, selectively killing cancer cells
while leaving normal cells unharmed.

4) Berkson, Burton M., Daniel M. Rubin, and Arthur
J. Berkson. “Revisiting the ALA/N (α-Lipoic Acid/Low-
Dose Naltrexone) protocol for people with metastatic
and nonmetastatic pancreatic cancer: a report of 3
new cases.” Integrative cancer therapies 8.4 (2009):
416-422.

 

p. 90
Low-Dose Naltrexone (LDN)

LDN blocks the opiate growth factor
receptor (OGFr) implicated in breast and
pancreatic cancer proliferation. (15)

15) Li, Zijian, et al. “Low-dose naltrexone (LDN): A
promising treatment in immune-related diseases and
cancer therapy.” International immunopharmacology
61 (2018): 178-184.

p 90
Similarly, Dr. Zagon also studied OGF in pancreatic
and ovarian cancer. (17–18)

17) Zagon, Ian S., and Patricia J. McLaughlin. “Opioid
growth factor and the treatment of human pancreatic
cancer: a review.” World Journal of Gastroenterology:
WJG 20.9 (2014): 2218.

18) Zagon, Ian S., Renee Donahue, and Patricia J.
McLaughlin. “Targeting the opioid growth factor:
opioid growth factor receptor axis for treatment of
human ovarian cancer.” Experimental Biology and
Medicine 238.5 (2013): 579-587

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)
A 46-year-old male sought medical attention
for abdominal pain, which was biopsy-proven
to be pancreatic cancer metastatic to the liver.
The patient was then treated with conventional
chemotherapy (gemcitabine and carboplatin),
which caused leukopenia and thrombocytopenia.
The patient tolerated the chemotherapy
poorly, seeking a second opinion from a different
oncologist who advised “any further treatment
would ultimately be fruitless.” (24)
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). There was also dietary and lifestyle
modification. This treatment program
resulted in comparatively “stable disease for
more than a 3-year period.” (24)

23) Berkson, Burton M., Daniel M. Rubin, and Arthur
J. Berkson. “Revisiting the ALA/N (α-Lipoic Acid/Low-
Dose Naltrexone) protocol for people with metastatic
and nonmetastatic pancreatic cancer: a report of 3
new cases.” Integrative cancer therapies 8.4 (2009):
416-422.

24) Berkson, Burton M., Daniel M. Rubin, and Arthur
J. Berkson. “The long-term survival of a patient with
pancreatic cancer with metastases to the liver after
treatment with the intravenous α-lipoic acid/low-dose
naltrexone protocol.” Integrative cancer therapies 5.1
(2006): 83-89.

p 93
In 2014, Dr. Bradley Hanberry, using two
cancer cell lines, pancreatic cancer and neuroblastoma,
found that high-dose thiamine
reduced cancer cell proliferation. The mechanism
was analogous to dichloroactetate (DCA),
as both are glycolysis inhibitors. (40)

p 113
48) Du, Juan, et al. “Mechanisms of ascorbate-induced
cytotoxicity in pancreatic cancer.” Clinical Cancer
Research 16.2 (2010): 509-520.

p 119
Pancreatic Cancer Stem Cell Model—Dr. Sancho

In 2015, Dr. Patricia Sancho et al. studied a
pancreatic cancer cell model and found metformin
to be an effective CSC agent. Dr. Sancho’s
group found that CSCs are a minor population
(0.001 to 0.1%) of the entire cancer. The stem
cells had a low proliferation rate, remaining
dormant, and a high level of drug resistance
to chemotherapy. They displayed stem cell
surface markers such as CD44 and CD133 and
(ALDH). Signaling pathways for CSCs include
Wnt, Notch, and Hedgehog (15).

Dr. Sancho et al. were
disappointed to find that pancreatic tumors
developed resistance to metformin and then
progressed to a more aggressive form in cancer
xenografts.

15) Patricia Sancho, et al. “MYC/PGC-1a Balance
Determines the Metabolic Phenotype and Plasticity
of Pancreatic Cancer Stem Cells.” Cell Metabolism 22
(2015): 1-16.

p 135
Berberine, “An Epiphany Against Cancer”—
A Natural Wnt Pathway Inhibitor

In 2014, Dr. Park showed that berberine
downregulates CSC-associated genes in pancreatic
cancer cell lines. (52)

52) Park, S. H., J. H. Sung, and Namhyun Chung.
“Berberine diminishes side population and down-regulates
stem cell-associated genes in the pancreatic cancer
cell lines PANC-1 and MIA PaCa-2.” Molecular and
Cellular Biochemistry 394.1-2 (2014): 209-215.

As noted in a previous chapter, berberine
and metformin are both OXPHOS inhibitors via
inhibition of mitochondrial complex 1 of the
electron transport chain (ETC).

 

p 136
Pancreatic Cancer Stem Cells—Sonic Hedgehog Pathway

In 2009, Dr. Kallifatidis studied sulforaphane
in a pancreatic cancer cell line, finding efficacy
against CSCs:

Sulforaphane targets pancreatic tumor-initiating
cells by NF-kappa-B-induced
anti-apoptotic signaling …” (66)

66) Kallifatidis G, Rausch V, Baumann B, et al.
Sulforaphane targets pancreatic tumour-initiating cells
by NF-kappaB-induced antiapoptotic signalling. Gut.
2009; 58:949–63.

p 137
In 2012, Dr. Rodova studied inhibition of
pancreatic CSCs by sulforaphane (SFN), finding
inhibition of the sonic hedgehog pathway
as the main mechanism, writing:

Thus Sulforaphane potentially represents
an inexpensive, safe and effective alternative
for the management of pancreatic
cancer. (67)

67) Rodova, Mariana, et al. “Sonic hedgehog signaling
inhibition provides opportunities for targeted therapy
by sulforaphane in regulating pancreatic cancer stem
cell self-renewal.” PloS one 7.9 (2012): e46083.

p 137
Sulforaphane for CSCs: Cancer Cell Types

Sulforaphane has been studied and found
effective in preclinical in vitro and in vivo studies
in various CSC types, and synergizes with
chemotherapy and other natural substances:
• Pancreatic cancer stem cells (67)

p 145
Sulforaphane Synergy with Quercetin

75) Srivastava, Rakesh K., et al. “Sulforaphane synergizes
with quercetin to inhibit self-renewal capacity of
pancreatic cancer stem cells.” Frontiers in Bioscience
(Elite edition) 3 (2011): 515.

p 152
Sulfasalazine has been studied in other cancer
cell types, including
• Pancreatic cancer (14)

14) Lo, M., et al. “Potential use of the anti-inflammatory
drug, sulfasalazine, for targeted therapy of pancreatic
cancer.” Current Oncology 17.3 (2010): 9-16.

p 152 Question of Impairment of T Cell Immunity

In 2019, Dr. Michael Arensman et al. studied
this question using an in vitro and in vivo
mouse model in which the xCT protein in pancreatic
cancer tumor cells was genetically
deleted. In addition, xCT knockout mice were
also studied. They were quite surprised to find
that “knocking out” the xCT cystine importer in
genetically modified mice did not impair T cell
anti-tumor immunity, writing:

Surprisingly, T cell proliferation and anti-tumor
immunity were not impaired in xCT
knockout mice, leading us to evaluate the
possibility of combining systemic xCT loss
with the immunotherapeutic agent anti–
CTLA-4… Surprisingly, although deletion
of the xCT led to impaired tumor growth,
T cell proliferation was unaffected…. The
combination of xCT deletion with anti–
CTLA-4 resulted in a remarkable increase in
durable responses, suggesting that systemic
inhibition of xCT is a viable strategy
to expand the efficacy of anti-cancer
immunotherapies. (23)

 

 

p 155
Chloroquine is Cancer Stem Cell Agent
Dr. Dong Soon Choi et al. report (2014) that
Chloroquine is an effective CSC agent. (51)
Chloroquine as an anti-CSC agent has been
studied in the following CSCs via inhibition of
autophagy:

p 155
Pancreatic cancer stem cells (55–57)

55) Balic, Anamaria, et al. “Chloroquine targets pancreatic
cancer stem cells via inhibition of CXCR4 and
hedgehog signaling.” Molecular cancer therapeutics
13.7 (2014): 1758-1771.

56) Frieboes, Hermann B., et al. “Chloroquine-Mediated
Cell Death in Metastatic Pancreatic Adenocarcinoma
through Inhibition of Autophagy.” JOP. Journal of the
Pancreas 15.2 (2014): 189-197.

57) Balic, Anamaria, Morten Dræby Sørensen, and
Christopher Heeschen. “Old drugs for new purposes-
chloroquine targets metastatic pancreatic cancer
stem cells & their microenvironment.” Cancer Cell
Microenviron. 1 (2014): e227.

 

p 158

ATRA Modulates Gene
Expression in Cancer Cells

In 2019, Dr. Lara Lima et al. reviewed 31 preclinical
“Vesinoid® (ATRA) studies involving
nine different human cancer types (neuroblastoma,
acute myeloid leukemia, breast cancer,
lung cancer, pancreatic cancer, glioma, glioblastoma,
embryonal carcinoma, and colorectal
cancer) treated with ATRA at concentrations
ranging from 10–100 μmol/L for times ranging
from 1–21 days. They state:

miRNAs are endogenous, small, noncoding
RNAs that regulate gene expression by
binding to their target mRNAs [messenger
RNA], leading to degradation and/or
translational repression. (103)

p 164
93) Herreros-Villanueva, Marta, Tze-Kiong Er, and Luis
Bujanda. “Retinoic acid reduces stem cell–like features
in pancreatic cancer cells.” Pancreas 44.6 (2015):
918-924.

 

p 170
Effective for Oral Administration

Another example is the 2004 study by Dr.
Hiroyasu Esumi et al. in which pyrvinium was
found active both by oral gavage and subcutaneous
injection in a mouse xenograft model of
pancreatic cancer. The in vitro portion of the
study showed pyrvinium was extremely toxic
to pancreatic cancer cells (in vitro) in a glucose-
free medium under conditions of glucose
starvation. One might speculate that glucose
starvation shifted the cancer cells to OXPHOS
metabolism (pyrvinium being effective here),
while abundant glucose shifted the cells to
GLYCOLYSIS (the Warburg effect), making pyrvinium
ineffective.

Regarding the in vivo study, Dr. Esumi et
al. write that pyrvinium was effective for both
routes of administration in mice:
Although PP [pyrvinium] has been claimed
not to be absorbed by the mammalian
intestine, preliminary tests indicated that
it is absorbed, because the urine of a
human turned red after oral consumption
of 100mg of a commercial anthelminthic
preparation [our unpublished observation].
We examined the effect of orally administered
PP on tumor growth in nude mice
bearing PANC-1 tumors. The results clearly
demonstrate that PP exerted clear anti-tumor
activity on the PANC-1 cells in nude
mice…. The dose of PP administered was
100 μg / mouse / day…. PP was also found
to exert anti-tumor activity against human
pancreatic cancer cell line PANC-1 in nude
mice and SCID mice when it was administered
subcutaneously or orally. (31)

p 175
One such study, done in 2019 by Dr. Kelvin
Tsoi et al. in Hong Kong over a ten-year period,
found that aspirin users had significant reduction of cancers
in liver (RR:0.49), stomach (RR: 0.42), colorectum (RR:
0.71), lung (RR: 0.65), pancreas (RR: 0.54),
oesophagus (RR: 0.59) and leukaemia (RR:
0.67). [Note: RR of 0.67 = 33% less cancer,
etc. Percent cancer is 1-RR.] (7)

p 177
A similar previous study was done in 2015
by Dr. Yiyao Zhang et al. using pancreatic cancer
cells from surgical resections of pancreatic
cancer. These studies were done using in vitro
and in vivo mouse xenografts and found that
aspirin decreased the number of cancer stem
cells and overcame (gemcitabine) chemotherapy
resistance. This is accomplished by disrupting
NF-kB/IL6 signaling. (12)

12) Zhang, Yiyao, et al. “Aspirin counteracts cancer
stem cell features, desmoplasia and gemcitabine resistance
in pancreatic cancer.” Oncotarget 6.12 (2015):
9999.

p 178 Combination of Metfromin and Aspirin

In 2014 and 2015, Dr. Wen Yue et al. studied
the combination of metformin and aspirin in a
pancreatic cancer cell line in vitro and in vivo.
This combination downregulated the AMPKmTOR
pathway and suppressed the anti-apoptotic
protein BCL-2. (36–38)

In 2014 and 2015, Dr. Wen Yue et al. studied
the combination of metformin and aspirin in a
pancreatic cancer cell line in vitro and in vivo.
This combination downregulated the AMPKmTOR
pathway and suppressed the anti-apoptotic
protein BCL-2. (36–38)

They then used RNA transcriptome analysis
to evaluate the genetic expression of the cancer
cells in response to treatment:
We conducted a transcriptomic analysis
using RNA sequencing to assess the
differential gene expression induced
by metformin (5 milliMolar) and aspirin
(2 milliMolar), alone or in combination,
after treatment of PANC-1 cells [pancreatic
cancer] for 48 hours. (38)

While singly there was only slight change
in the genetic expression of the cancer cells,
the combination treatment induced a dramatic
change, with over a thousand genes affected.
While metformin or aspirin alone only
slightly changed the transcriptome profile
of PANC-1 cells (149 and 12 genes, respectively),
the combination of metformin and
aspirin dramatically affected the transcription
of 1,105 genes. (38)

36) Yue, Wen, et al. “Repurposing of metformin and
aspirin by targeting AMPK-mTOR and inflammation for
pancreatic cancer prevention and treatment.” Cancer
prevention research 7.4 (2014): 388-397.

37) Yue, Wen, et al. “Metformin combined with aspirin
significantly inhibit pancreatic cancer cell growth in
vitro and in vivo by suppressing anti-apoptotic proteins
Mcl-1 and Bcl-2.” Oncotarget 6.25 (2015): 21208.

38) Yue, Wen, et al. “Transcriptomic analysis of pancreatic
cancer cells in response to metformin and aspirin:
an implication of synergy.” Scientific reports 5 (2015):
13390.

p 181
12) Zhang, Yiyao, et al. “Aspirin counteracts cancer
stem cell features, desmoplasia and gemcitabine resistance
in pancreatic cancer.” Oncotarget 6.12 (2015):
9999.

p 187-188
Pancreatic Cancer Stems Cell Use OXPHOS

In 2015, Dr. Patricia Sancho et al. studied
metformin’s effects on pancreatic CSCs, finding
that metformin targets pancreatic cancer
stem cells (CSCs) but not their differentiated
non-cancer stem cells (non-CSCs). Dr. Sancho
and colleagues’ study of pancreatic cancer
demonstrated that tumor bulk, or non CSCs,
are highly glycolytic. On the other hand, CSCs
use OXPHOS and are dependent on oxidative
metabolism with “very limited metabolic plasticity.”
Thus, mitochondrial inhibition by metformin
creates an energy crisis and induces
CSC apoptosis. Dr. Sancho et al. state that cancer
stem cells are heterogeneous, and become
metformin-resistant over time. These resistant
cancer stem cells have an intermediate “glycolytic/
respiratory phenotype.” In other words,
they use both the GLYCOLYSIS and OXPHOS
pathways. Dr. Sancho et al. write that “resis
tant Cancer Stem Cell (CSC) clones eventually
emerge with intermediate glycolytic/respiratory
phenotype.”(22) They have replicated
the findings of the Lisanti Group, which found
that long-term treatment of cancer stem cells
(OXPHOS phenotype) with doxycycline resulted
in emergence of a doxycycline- resistant (DOXR)
cancer stem cell type, which acquired a
purely glycolytic phenotype, also called the
Warburg phenotype. (23)

p 188
OXPHOS Required for Cancer
Stem Cell Functionality

Similarly, Dr. Sancho’s group found that
cancer stem cells developed resistance to
metformin over time, a problem resolved by
combining metformin with c-Myc inhibitor
drug, overcoming the resistant phenotype.
They write that “high OXPHOS activity is mandatory
for full cancer stem cell functionality”
and that combining metformin with c-Myc inhibition,
prevented or reversed, respectively,
resistance to metformin by enforcing their
dependence on OXPHOS, suggesting a new
multimodal approach for targeting the
distinct metabolic features of pancreatic
CSCs [cancer stem cells] … increased MYC
expression is indeed the mechanistic link
for the altered/distinct metabolic phenotype
of resistant CSC with enhanced glycolysis.
Notably, MYC inhibition or knockdown
also enhanced stemness of resistant CSCs,
as evidenced by increased pluripotency
gene expression, self-renewal capacity, and
CD133+cell content. These data confirm
that high OXPHOS activity is mandatory
for full CSC functionality. (22)

Note: The c-Myc oncogene orchestrates the
Warburg Effect (i.e. GLYCOLYSIS). Inhibiting
c-Myc will inhibit GYCOLYSIS. C-Myc is also a
downstream target of the Wnt/beta-catenin
pathway, so all Wnt inhibitors are also c-Myc
inhibitors. (24–25) Other C-Myc inhibitors
include artesunate, pterostilbene, sulforaphane,
and diclofenac.

p 189

Low c-Myc in Cancer Stem Cells, High
c-Myc in Glycolytic Cancer Cells

Activation of the c-Myc protein pathway promotes
a glycolytic (Warburg-like) cell phenotype.
In 2015, Dr. Sancho et al. studied c-Myc in
pancreatic cancer stem cells, finding that LOW
Myc expression allowed high peroxisome proliferator-
activated receptor (PPAR) activity,
resulting in increased mitochondrial biogenesis,
enhanced mitochondrial activity (OXPHOS),
and low mitochondrial reactive oxygen Species
(ROS), all prerequisites for cancer cell “stemness.”
Suppression (or inhibition) of c-Myc to
low levels maintained the cancer stem cells,
and rendered them unable to switch over to
a glycolytic phenotype (the Warburg Effect),
thus making the cancer stem cells susceptible
to mitochondrial inhibition with metformin
and menadione (vitamin K). (22)

22) Sancho, Patricia, et al. “MYC/PGC-1a Balance
Determines the Metabolic Phenotype and Plasticity
of Pancreatic Cancer Stem Cells.” Cell Metabolism 22
(2015): 1-16

Important: Pancreatic cancer stem cells have
low c-Myc activity, preventing a switch to the
glycolytic phenotype.

Wnt Inhibitors Are Also c-Myc Inhibitors
Other c-Myc inhibitors include all OXPHOS/
Wnt inhibitors drugs, such as niclosamide, ivermectin,
pyrvinium, aspirin, celecoxib etc. (28)

28) Ahmed, Kamal, et al. “A second WNT for old drugs:
Drug repositioning against WNT-dependent cancers.”
Cancers 8.7 (2016): 66.

The signaling proteins c-myc, cyclin D1, and
axin are downstream from Wnt pathway signaling,
so all Wnt inhibitors also inhibit c-myc
and cyclin D1.

p 190
Metformin Synergizes with
GLYCOLYSIS Inhibition

As mentioned above, pancreatic cancer stem
cells preferentially use mitochondrial OXPHOS
(oxidative phosphorylation) pathways for their
energetic, migratory, and metastatic capacity.
Indeed, Dr. Diana Whitaker-Menezes et al. in
Cell Cycle (2011) reported that hyperactive
oxidative mitochondrial metabolism in cancer
stem cells was blocked by metformin, inducing
a purely glycolytic phenotype in surviving
cancer stem cells, now rendered sensitive to
glucose starvation with a second agent such as
2DG or high-dose intravenous vitamin C, creating
synthetic lethality. (33–34).

33) Whitaker-Menezes, Diana, et al. “Hyperactivation
of oxidative mitochondrial metabolism in epithelial
cancer cells in situ: visualizing the therapeutic effects
of metformin in tumor tissue.” Cell cycle 10.23 (2011):
4047-4064.

34) Menendez, Javier A., et al. “Metformin is synthetically
lethal with glucose withdrawal in cancer cells.”
Cell cycle 11.15 (2012): 2782-2792.

Other glycolysis
inhibitors, such as DCA or diclofenac
might be considered instead of 2DG. For example,
in 2018, Dr. Valeria Gerthofer et al. studied
the anti-cancer effects of metformin on a
glioblastoma cell line. Considerable synergy
was observed with the addition of a glycolysis
inhibitor, diclofenac. This is expected, since the
OXPHOS inhibitor metformin probably induced
a glycolytic cell line, now susceptible to inhibition
by the diclofenac. (35)

35) Gerthofer, Valeria, et al. “Combined modulation
of tumor metabolism by metformin and diclofenac in
glioma.” International journal of molecular sciences
19.9 (2018): 2586.

 

p 191
Metformin Epigenetic Effects

In 2012, Dr. Bin Bao et al. studied the
anti-cancer stem cell ability of metformin in a
pancreatic cancer cell line, finding metformin
decreased the cancer stem cell markers CD44,
EpCAM, EZH2, Notch-1, Nanogand, and Oct4.
Metformin also caused:

re-expression of [micro- RNA’s] miRNAs
(let-7a ,let-7b, miR-26a, miR-101, miR-200b,
and miR-200c) that are typically lost in pancreatic
cancer and especially in pancreatospheres
[stem cells]. These results clearly
suggest that the biologic effects of metformin
are mediated through re-expression
of miRNAs and decreased expression of
[Cancer Stem Cell] CSC-specific genes,
suggesting that metformin could be useful
for overcoming therapeutic resistance of
pancreatic cancer cells. (36)

Note: Micro RNA (MiRNA) plays a role in the
post-transcriptional regulation of protein
expression.

36) Bao, Bin, et al. “Metformin inhibits cell proliferation,
migration and invasion by attenuating CSC function
mediated by deregulating miRNAs in pancreatic
cancer cells.” Cancer prevention research 5.3 (2012):
355-364.

p 198
Metformin Synergy with Simvastatin

Statin drugs were originally developed for
lowering cholesterol by blocking the enzyme
HMG-CoA as well as the mevalonate pathway.
Over many years of clinical use, it was discovered
that statin drugs have “pleotropic effects,”
namely anti-inflammatory and antimicrobial
effects. Activation of the cellular NF-kB inflammatory
pathway is potently inhibited by statin
drugs. Recently, there has been interest
in statins as repurposed anti-cancer agents.
Statin-drug use in combination with metformin
prolonged survival in resectable pancreatic
cancer patients. (71–73)

71) Babcook, Melissa A., et al. “Synergistic simvastatin
and metformin combination chemotherapy for
osseous metastatic castration-resistant prostate cancer.”
Molecular cancer therapeutics 13.10 (2014):
2288-2302.

72) Kozak, Margaret M., et al. “Statin and metformin
use prolongs survival in patients with resectable pancreatic
cancer.” Pancreas 45.1 (2016): 64-70.

73) Jian-Yu, E., et al. “Effect of metformin and statin
use on survival in pancreatic cancer patients: a systematic
literature review and meta-analysis.” Current
medicinal chemistry 25.22 (2018): 2595-2607.

 

p 209
Cancer Stem Cell Metabolism: OXPHOS or Glycolysis?

What is the metabolic phenotype of the cancer
stem cells? Is it OXPHOS or GLYCOLYSIS?
According to Dr. Patricia Sancho et al. in 2015,
the metabolic phenotypes vary according to
cancer cell type. In breast cancer, they are predominantly
GLYCOLYSIS. In pancreatic cancer,
glioblastoma, and leukemia, they rely on mitochondrial
OXPHOS. Dr. Sancho’s group write:

The metabolic phenotype of CSCs [cancer
stem cells] appears to vary across tumor
types. While in breast cancer and nasopharyngeal
carcinoma CSCs were found to be
predominantly glycolytic [GLYCOLYSIS]….
CSCs in pancreatic cancer, glioblastoma
and leukemia appear to rely on mitochondrial
OXPHOS (18–20)

18) Sancho, Patricia, et al. “MYC/PGC-1α balance
determines the metabolic phenotype and plasticity
of pancreatic cancer stem cells.” Cell metabolism 22.4
(2015): 590-605.

19) Puigserver, Pere. “PGC1a at the Nexus of Cancer
Stem Cell Fates.” Free Radical Biology and Medicine
128 (2018): S14.

20) Sun, Haoran, et al. “Therapeutic strategies targeting
cancer stem cells and their microenvironment.”
Frontiers in oncology 9 (2019): 1104.

p 212
32) Zhu, Haitao, et al. “Role of the Hypoxia-inducible
factor-1 alpha induced autophagy in the conversion of
non-stem pancreatic cancer cells into CD133+ pancreatic
cancer stem-like cells.” Cancer cell international
13.1 (2013): 119.

p 212

35) Renz, Bernhard W., et al. “Repurposing established
compounds to target pancreatic cancer stem cells
(CSCs).” Medical Sciences 5.2 (2017): 14.

Pterostilbene Anti-Cancer Effects

Numerous studies have been done showing
the anti-cancer effects of pterostilbene for:
• Pancreatic cancer (48–49)

48) McCormack, Denise E., Debbie E. McDonald,
and David W. McFadden. “Pterostilbene Induces
Mitochondrially-Derived Apoptosis in Pancreatic
Cancer Cells by Increasing MnSOD Activity and Release
of Cytochrome C and Smac/DIABLO.” Gastroenterology
140.5 (2011): S-1026.

49) Mannal, Patrick W., et al. “Pterostilbene inhibits
pancreatic cancer in vitro.” Journal of Gastrointestinal
Surgery 14.5 (2010): 873-879.

 

Pterostilbene is protective of the following
organ systems:
• Liver, from acetaminophen induced toxicity
(76)
• Pancreatic beta-cells, from apoptosis in
Type I diabetics (77–78)

77) Bhakkiyalakshmi, Elango, et al. “Therapeutic
potential of pterostilbene against pancreatic beta‐cell
apoptosis mediated through N rf2.” British journal of
pharmacology 171.7 (2014): 1747-1757.

78) Sireesh, Dornadula, et al. “Role of pterostilbene in
attenuating immune mediated devastation of pancreatic
beta cells via Nrf2 signaling cascade.” The Journal
of nutritional biochemistry 44 (2017): 11-21.

80) Li, Jin, et al. “Blueberry component pterostilbene
protects corneal epithelial cells from inflammation via
anti-oxidative pathway.” Scientific Reports 6 (2016):
19408.

p 226
Boswellia Effective for Various Cancer Cell Types

• Pancreatic cancer (44)

44) Park B, Prasad S, Yadav V, Sung B, Aggarwal BB.
Boswellic acid suppresses growth and metastasis
of human pancreatic tumors in an orthotopic nude
mouse model through modulation of multiple targets.
PLoS One. 2011; 6(10):e26943

 

p 227
3) Ding, Xiaoling, et al. “Enhancing antitumor effects in
pancreatic cancer cells by combined use of COX-2 and
5-LOX inhibitors.” Biomedicine & Pharmacotherapy
65.7 (2011): 486-490.

p 228
20) Saha, Sounik, et al. “Gold nanoparticle reprograms
pancreatic tumor microenvironment and inhibits
tumor growth.” ACS Nano 10.12 (2016): 10636-10651.

p 231

What is Epithelial Growth Factor (EGF) ?

EGFR is a cancer cell surface receptor (a
tyrosine kinase receptor) responsible for
stimulating cell growth, proliferation, and
cell replication and for inhibiting autophagy.
Hyperactive EGF signaling is often found in epithelial
cell types such as lung, breast, pancreas,
colon, bladder, kidney, prostate, ovary, and
glioblastoma, leading to adoption of Warburg type
metabolism, which is highly glycolytic
with production of lactate and stimulation of
angiogenesis. EGFR activation induces HIF-1
(hypoxia-inducible factor), which increases
transcription of glycolytic enzymes and upregulates
production of hexokinase 2. (6–9)

6) Sankara Narayanan, Nitin. Role of Epidermal Growth
Factor Receptor in Tumor Cell Metabolism. Diss.
University of Cincinnati, 2014.

7) Freudlsperger, Christian, et al. “EGFR–PI3K–AKT–
mTOR signaling in head and neck squamous cell carcinomas:
attractive targets for molecular-oriented
therapy.” Expert opinion on therapeutic targets 15.1
(2011): 63-74.

8) Bhat, Firdous Ahmad, et al. “Quercetin reverses
EGF-induced epithelial to mesenchymal transition
and invasiveness in prostate cancer (PC-3) cell line via
EGFR/PI3K/Akt pathway.” The Journal of Nutritional
Biochemistry 25.11 (2014): 1132-1139.

9) Karar, Jayashree, and Amit Maity. “PI3K/AKT/mTOR
pathway in angiogenesis.” Frontiers in molecular neuroscience
4 (2011): 51.

p 238-239

Cannabinoids have been studied in these
cancer cell lines:
• Pancreatic cancer (36)

36) Sharafi, Golnaz, Hong He, and Mehrdad Nikfarjam.
“Potential use of cannabinoids for the treatment of
pancreatic cancer.” Journal of pancreatic cancer 5.1
(2019): 1-7.

p 260
Antimalarial Drugs Are Also Anti-Cancer Drugs

Over the years, it was discovered that artemisinin
is also a very effective anti-cancer drug.
In 2015, Dr. A. K. Das reported that artemisinin
(and its derivatives) are effective against 55
cancer cell lines with inhibitory effects against
pancreatic cancer, osteosarcoma, lung cancer,
colon, melanoma, breast, ovarian, prostate,
central nervous system, lymphoma, leukemia
and renal cancer cells. In addition, artesunate
potentiated the effect of the common chemotherapy
drug doxorubin in a drug-resistant leukemia
line. (3)

3) Das, A. K. “Anticancer effect of antimalarial artemisinin
compounds.” Annals of medical and health
sciences research 5.2 (2015): 93-102.

p 267

A 2012 study by Dr. Mariana Rodova et
al. showed that sulforaphane is effective as
anti-cancer treatment for pancreatic cancer
stem cells via the blockade of hedgehog signaling.
(66)

66) Rodova, Mariana, et al. “Sonic hedgehog signaling
inhibition provides opportunities for targeted therapy
by sulforaphane in regulating pancreatic cancer stem
cell self-renewal.” PloS one 7.9 (2012): e46083

p 281

78) Lo, M., et al. “Potential use of the anti-inflammatory
drug, sulfasalazine, for targeted therapy of pancreatic
cancer.” Current Oncology 17.3 (2010): 9-16.

p 319
Mutated P53 Predicts Poor Prognosis

The P53 gene has been coined “the guardian
of the genome” because it protects the cell
from oncogenic transformation. About half of
all cancers have a mutated P53 gene, which
predicts poor prognosis with short survival.
The mutated P53 cancers are more aggressive,
with rapid progression to metastatic disease
and resistance to chemotherapy. This is true
for all cancer cell types—hematologic cancers,
pancreatic, lung, endometrial, ovarian, breast,
etc. (56–58)

56) D’Orazi, Gabriella, and Mara Cirone. “Mutant p53
and cellular stress pathways: a criminal alliance that
promotes cancer progression.” Cancers 11.5 (2019):
614

57) Mantovani, Fiamma, Dawid Walerych, and
Giannino Del Sal. “Targeting mutant p53 in cancer: a
long road to precision therapy.” The FEBS journal 284.6
(2017): 837-850.

58) 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
Benzimidazoles for Pancreatic Cancer

In 2019, Dr. Rosalba Florio et al. studied the
“effects of FDA-approved benzimidazole-based
anthelminthics fenbendazole, mebendazole,
oxibendazole and parbendazole in PC (pancreatic
cancer) cell lines.” (62)

62) Florio, Rosalba, et al. “The Benzimidazole-Based
Anthelmintic Parbendazole: A Repurposed Drug
Candidate That Synergizes with Gemcitabine in
Pancreatic Cancer.” Cancers 11.12 (2019): 2042.

Parbendazole was the most potent of the
group, with IC50 values (50% inhibitory concentration)
in the nanomolar range, inducing
“mitotic catastrophe“ in the cancer cells. Dr.
Floria and colleagues concluded:

This is the first study providing evidence
that parbendazole as a single agent, or in
combination with gemcitabine, is a repurposing
candidate in the currently dismal PC
(pancreatic cancer) therapy. (62)

62) Florio, Rosalba, et al. “The Benzimidazole-Based
Anthelmintic Parbendazole: A Repurposed Drug
Candidate That Synergizes with Gemcitabine in
Pancreatic Cancer.” Cancers 11.12 (2019): 2042.

p 323
46) Rodova, Mariana, et al. “Sonic hedgehog signaling
inhibition provides opportunities for targeted therapy
by sulforaphane in regulating pancreatic cancer stem
cell self-renewal.” PloS one 7.9 (2012).

 

p 325
I had the pleasure of attending a presentation
by the late Nicholas Gonzalez, MD, a keynote
speaker at the Boulderfest Conference,
July 17–20, 2008, in Denver Colorado. Sadly,
Dr. Gonzalez passed away unexpectedly seven
years later, July 2015. For many productive
years, he practiced integrative oncology in his
Manhattan office, treating advanced cancer
patients successfully with high-dose pancreatic
enzyme capsules taken orally. (1–4)

1) Gonzalez, Nicholas J., and Linda L. Isaacs. “The
Gonzalez therapy and cancer: A collection of case
reports.” Alternative Therapies in Health and Medicine
13.1 (2007): 46.

2) Isaacs, Linda L. “The Gonzalez Best Case Series
Presentation to the NCI: 25 Cases, 25 Years Later.”
Alternative therapies in health and medicine 25.4
(2019): 12-14.

3) Isaacs, Linda L. “An Enzyme-Based Nutritional
Protocol in Metastatic Cancer: Case Reports Of A
Patient With Colon Cancer And A Patient With Lung
Cancer.” Alternative therapies in health and medicine
25.4 (2019): 16-19.

4) Gonzales NJ, Isaacs LL. Evaluation of pancreatic proteolytic
enzyme treatment of adenocarcinoma of the
pancreas, with nutrition and detoxification support.
Nutr Cancer 1999; 33(2):117-124.

 

p 326
Pancreatic Enzymes on Day 56

John Beard observed that the trophoblast
cells transform from a malignant, invasive cell
type into a mature well-behaved cell type. This
occurs on Day 56 of gestation, and also coincides
with the appearance of enzyme granules
(zymogen granules) in the fetal pancreas.

After this “Eureka Moment”, Dr. Nicholas
González developed a protocol for treatment
of cancer using pancreatic enzymes, finding
patient outcomes better than the national average.
Other researchers performed preclinical
studies confirming the hypothesis, and a number
of case reports appeared in the medical literature.
(23–34)

23) Gonzalez, N. J. “Nicholas Gonzalez, MD: an enzyme
approach to cancer. Interview by Karen Burnett.”
Alternative therapies in health and medicine 18.6
(2012): 54.

24) Gonzalez, Nicholas J. What Went Wrong: the truth
behind the clinical trial of the enzyme treatment of
cancer. New Spring Press, 2012.

 

Pilot study of the Enzyme Treatment
of Pancreatic Cancer

In 1999, González published a 2-year pilot
study of 10 patients with inoperable advanced
pancreatic cancer treated with large doses of
orally ingested pancreatic enzymes. Results
showed 80% survival after 1 year, 45% survival
after 2 years and 36% survival after 3 years. (4)

These results are far above the 25% one
year, 10% two year, and 6 % three-year survival
reported in the National Cancer Data Base for
inoperable pancreatic cancer. (25)

25) Niederhuber, John E., Murray F. Brennan, and
Herman R. Menck. “The national cancer data base
report on pancreatic cancer.” Cancer 76.9 (1995):
1671-1677.

p 328
No Coexistence of Cancer with
Circulating Enzymes of Pancreatitis
One last point I am compelled to mention.

During my 30-year career as a radiologist, much
of my time was spent reading images of metastatic
cancer on CAT scans. One thing I noticed
was that I never witnessed the presence of metastatic
cancer in patients who had pancreatic
enzymes circulating freely in the bloodstream
from acute or chronic pancreatitis. (Excluded,
of course, was focal pancreatitis caused by an
obstructed pancreatic duct due to a small pancreatic
cancer.) Thus, I had independently confirmed
the major tenet of John Beard and Ernst
Krebs many years before I even heard of the
trophoblastic theory of cancer.

p331
34) Wald M, Poucková P, Hloušková D, Altnerová M,
Olejár T. The influence of trypsin, chymotrypsin and
papain on the growth of human pancreatic adenocarcinoma
transplanted to nu/nu mice. The European
Journal of Cancer 1999; 35(4), No. 543:148.

p 348
17) Chin, Ken Min, Chung Yip Chan, and Ser Yee Lee.
“Spontaneous regression of pancreatic cancer: A case
report and literature review.” International journal of
surgery case reports 42 (2018): 55-59.

p 361
Beta glucans benefits in various cancer cell
lines:

• Pancreatic cancer, synergy with gemcitabine
(36–37)

36) Suenaga, Shigeyuki, et al. “Active hexose-correlated
compound down-regulates HSP27 of pancreatic cancer
cells, and helps the cytotoxic effect of gemcitabine.”
Anticancer research 34.1 (2014): 141-146.

37) Tokunaga, Masayuki, et al. “Active hexose-correlated
compound down-regulates heat shock factor
1, a transcription factor for HSP27, in gemcitabine-resistant
human pancreatic cancer cells.” Anticancer
research 35.11 (2015): 6063-6067.

p 362 Combinations of AHCC and Wasabi
in Breast and Pancreatic Cell Lines—
Clinical Trial Under Way (51)

51) Corradetti, Bruna, et al. “Bioactive
Immunomodulatory Compounds: A Novel
Combinatorial Strategy for Integrated Medicine in
Oncology? BAIC Exposure in Cancer Cells.” Integrative
cancer therapies 18 (2019): 1534735419866908

p 368
48) Yanagimoto, Hiroaki, et al. “Alleviating effect of
active hexose correlated compound (AHCC) on chemotherapy-
related adverse events in patients with unresectable
pancreatic ductal adenocarcinoma.” Nutrition
and cancer 68.2 (2016): 234-240.

Vitamin D in Combination Therapies

In 2018, Dr. Stephen Bigelsen proposed
vitamin D (paricalcitol form) to upregulate
cytotoxic T lymphocytes in combination with
repurposed anti-cancer drugs such as hydroxychloroquine,
intravenous vitamin C, statins,
metformin, curcumin and aspirin for treatment
of pancreatic cancer, discussed elsewhere in
this book. (89–91)

89) Marcinkowska, Ewa, Graham R. Wallace, and
Geoffrey Brown. “The use of 1α, 25-dihydroxyvitamin
D3 as an anticancer agent.” International journal of
molecular sciences 17.5 (2016): 729.

90) Sarkar, Surojit, et al. “Role of vitamin D in cytotoxic
T lymphocyte immunity to pathogens and cancer.”
Critical reviews in clinical laboratory sciences 53.2
(2016): 132-145.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

91) Bigelsen, Stephen. “Evidence-based complementary
treatment of pancreatic cancer: a review of
adjunct therapies including paricalcitol, hydroxychloroquine,
intravenous vitamin C, statins, metformin,
curcumin, and aspirin.” Cancer management and
research 10 (2018): 2003.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

p 383

57) Barreto, Savio G., and Rachel E. Neale. “Vitamin
D and pancreatic cancer.” Cancer letters 368.1 (2015):
1-6.

58) Iqbal, Sarah, and Imrana Naseem. “Pancreatic
cancer control: is vitamin D the answer?” European
Journal of Cancer Prevention 25.3 (2016): 188-195.

59) Gilzad-Kohan, Hamed, Shabnam Sani, and Mehdi
Boroujerdi. “Calcitriol reverses induced expression
of efflux proteins and potentiates cytotoxic activity
of gemcitabine in capan-2 pancreatic cancer cells.”
Journal of Pharmacy & Pharmaceutical Sciences 20
(2017): 295-304.

 

p 402
Pancreatic Cancer—Autophagy
Inhibitor Combination

In 2019, Dr. Conan Kinsey et al. illustrated
this point nicely by adding an autophagy inhibitor
to pancreatic cancer cells, thereby pushing
them over the “apoptotic threshold.” Dr.
Kinsey’s group studied a pancreatic cancer cell
line in a mouse xenograft model, finding that
activation of the K-RAS/RAF/MEK/ERK signaling
pathway was key to cancer cell proliferation.
Paradoxically, inhibiting this key pathway
with a MEK inhibitor, the FDA-approved drug,
trametinib (trade name Mekinist), provided no
clinical benefit for pancreatic cancer patients.
The reason for this is that the pancreatic cancer
cells go into “protective autophagy” mode,
making them resistant to the cytotoxic effects
of the drug. Dr. Kinsey et al. then added the
autophagy inhibitor hydroxychloroquine
(HCQ) to the MEK inhibitor drug in the mouse
xenograft model, finding the combination was
now dramatically effective. They then tried the
experiment with other cancers—melanoma
and colorectal cancer—showing, similarly, very
effective response in the xenograft model with
this combination of drugs. (11)

11) Kinsey, Conan G., et al. “Protective autophagy
elicited by RAF→ MEK→ ERK inhibition suggests a
treatment strategy for RAS-driven cancers.” Nature
medicine 25.4 (2019): 620-627.

p 402
Dr. Kinsey Patient Case Report
on Pancreatic Cancer

Emboldened by successful xenograft studies,
Dr. Kinsey and his colleagues then treated
an 81-year-old refractory pancreatic cancer
patient in the clinic with the combination of
hydroxychloroquine (600 mg twice daily) along
with the MEK inhibitor (2mg of trametinib),
finding a remarkable 50% regression of tumor
size, resolution of debilitating pain, and dramatic
reduction in the CA19–9 tumor marker,
with no toxicity. Monthly ophthalmologic
exams and weekly electrocardiograms were
conducted showing no evidence of ocular or
cardiac toxicity.

p 402
Superior to Traditional Cytotoxic Chemotherapy

Dr. Kinsey et al. write that this autophagy
inhibitor combination is “likely to be superior
to traditional cytotoxic chemotherapy”:

Since both trametinib and hydroxychloroquine
are orally administered, FDAapproved
drugs…. these observations were
translated to the clinic for a single, heavily
pretreated PDA [pancreatic ductal adenocarcinoma]
patient. Remarkably, the T/HCQ
[trametinib/hydroxychloroquine] combination
resulted in substantial reduction in
this patient’s overall tumor burden, CA19–9
tumor marker, and resolution of debilitating
cancer pain. Moreover, the safety and
tolerability of the T/HCQ combination is
likely to be superior to traditional cytotoxic
chemotherapy for PDA patients. (11)

11) Kinsey, Conan G., et al. “Protective autophagy
elicited by RAF→ MEK→ ERK inhibition suggests a
treatment strategy for RAS-driven cancers.” Nature
medicine 25.4 (2019): 620-627.

p 402
Autophagy Clinical Trials a
Failure for Pancreatic Cancer

As mentioned above, preclinical studies
in pancreatic cancer using chloroquine and
hydroxychloroquine as autophagy inhibitors in
vitro and in vivo mouse xenograft studies have
been encouraging. However, human clinical trials
such as the 2020 study by Dr. Herbert Zeh
et al. have been disappointing. (13)

In 2020, Dr. Maria New and Sharon Tooze
write:

Despite the promising data in PDAC [pancreatic
ductal cancer] cell lines and mouse
xenografts showing that autophagy inhibition
reduces cell proliferation and tumor
size and prolongs mouse survival, clinical
outcomes in [human] autophagy inhibitor
trials have not seen an improvement on
standard-of-care treatment. (12)

12) New, Maria, and Sharon Tooze. “The Role of
Autophagy in Pancreatic Cancer—Recent Advances.”
Biology 9.1 (2020): 7.

13) Zeh, Herbert, et al. “A randomized phase II preoperative
study of autophagy inhibition with high-dose
hydroxychloroquine and gemcitabine/nab-paclitaxel in
pancreatic cancer patients.” Clinical Cancer Research
(2020).

14) Bigelsen, Stephen. “AB091. P063. Case report:
stage 4 pancreatic cancer to remission using paricalcitol
and hydroxychloroquine in addition to traditional
chemotherapy.” Annals of Pancreatic Cancer (2018).

p 403
Combination Therapy for Stage 4
Pancreatic Cancer: Hydroxychloroquine,
Vitamin D3, and Chemotherapy

One such case report of successful use
of “combination therapy” is that of Stephen
Bigelson, MD. In July 2016, Dr. Bigelson was
treated at Weill-Cornell Medical Center for
metastatic pancreatic cancer with peritoneal
spread and a massively elevated CA19–9
marker of 11,575.

Dr. Bigelson knew chemotherapy alone carried
a dismal prognosis. This prompted him to
perform a medical literature search looking for
combination therapies in addition to the conventional
chemotherapy drugs gemcitabine
and capecitabine. Dr. Bigelson was also treated
with the combination of intravenous paricalcitol
(Zemplar®), a vitamin D3 analog (25 mcg
three times a week), and the autophagy inhibitor,
hydroxychloroquine (600 mg twice a day).
Dr. Bigelson’s research paid off with a “complete
response” to treatment. As of 2018, he
was cancer free with a CA19–9 cancer marker
of only 15 U/ml. (down from 11,575), and a
follow-up CAT scan showing “no evidence of
disease” (NED). Based on large-scale studies,
the chances for such a favorable outcome is 1
in 340 or about 0.3 per cent. Dr. Bigelson also
references the repurposed use of intravenous
vitamin C, statins, metformin, curcumin and
aspirin as anti-cancer agents, all discussed
elsewhere in this book. (14–15)

14) Bigelsen, Stephen. “AB091. P063. Case report:
stage 4 pancreatic cancer to remission using paricalcitol
and hydroxychloroquine in addition to traditional
chemotherapy.” Annals of Pancreatic Cancer (2018).

15) Bigelsen, Stephen. “Evidence-based complementary
treatment of pancreatic cancer: a review of
adjunct therapies including paricalcitol, hydroxychloroquine,
intravenous vitamin C, statins, metformin,
curcumin, and aspirin.” Cancer Management and
Research 10 (2018): 2003.

16) Sherman, Mara H., et al. “Vitamin D receptor-mediated
stromal reprogramming suppresses pancreatitis
and enhances pancreatic cancer therapy.” Cell 159.1
(2014): 80-93.

17) Schwartz, Gary G., et al. “19-nor-1α,
25-Dihydroxyvitamin D2 (Paricalcitol) inhibits the proliferation
of human pancreatic cancer cells in vitro and
in vivo.” Cancer biology & therapy 7.3 (2008): 430-436

p 404
The Role of Vitamin D in Cancer Treatment

Paricalcitol is a synthetic version of vitamin
D3, considered safer and without the adverse
effects of hypercalcemia. Vitamin D analogs in
pancreatic cancer have a number of benefits.
One is the reduction in the protective layer of
stromal cells surrounding the cancer mass,
cloaking and protecting the mass from cytotoxic
drug treatment. The stromal cells (also
called stellate cells) have upregulated vitamin
D receptors, and treatment with vitamin D analogs
inactivates stromal cell production.
Vitamin D also upregulates the cell cycle
inhibitor proteins p21 and p27. Vitamin D
blocks the Wnt pathway, suppressing β-catenin
mediated gene transcription and reducing
inflammatory signaling. Vitamin D also inhibits
the mTOR pathway, a major pathway for cancer
cell growth and proliferation. Vitamin D
also acts as an immunomodulator, increasing
anti-tumor T cell penetration into the tumor
10–100 fold. Vitamin D is synergistic with vitamin
A and Metformin. Vitamin D is discussed in
more detail in Chapter 30. (16–28)

16) Sherman, Mara H., et al. “Vitamin D receptor-mediated
stromal reprogramming suppresses pancreatitis
and enhances pancreatic cancer therapy.” Cell 159.1
(2014): 80-93.

17) Schwartz, Gary G., et al. “19-nor-1α,
25-Dihydroxyvitamin D2 (Paricalcitol) inhibits the proliferation
of human pancreatic cancer cells in vitro and
in vivo.” Cancer biology & therapy 7.3 (2008): 430-436.

18) Bhattacharjee, V., Y. Zhou, and T. J. Yen. “A synthetic
lethal screen identifies the Vitamin D receptor
as a novel gemcitabine sensitizer in pancreatic cancer
cells.” Cell cycle 13.24 (2014): 3839-3856.

19) Yu, Wei-Dong, et al. “Calcitriol enhances gemcitabine
antitumor activity in vitro and in vivo by promoting
apoptosis in a human pancreatic carcinoma model
system.” Cell cycle 9.15 (2010): 3094-3101.

20) Javadinia, Seyed Alireza, et al. “Therapeutic potential
of targeting the Wnt/β‐catenin pathway in the
treatment of pancreatic cancer.” Journal of cellular
biochemistry 120.5 (2019): 6833-6840.

21) He, Weichun, et al. “Blockade of Wnt/β-catenin
signaling by paricalcitol ameliorates proteinuria and
kidney injury.” Journal of the American Society of
Nephrology 22.1 (2011): 90-103.

22) Guo, Li-Shu, et al. “Synergistic antitumor activity of
vitamin D3 combined with metformin in human breast
carcinoma MDA-MB-231 cells involves m-TOR related
signaling pathways.” Die Pharmazie-An International
Journal of Pharmaceutical Sciences 70.2 (2015):
117-122.

23) Abu el Maaty, Mohamed A., et al. “Differences
in p53 status significantly influence the cellular
response and cell survival to 1, 25‐dihydroxyvitamin
D3‐metformin cotreatment in colorectal cancer cells.”
Molecular carcinogenesis 56.11 (2017): 2486-2498.

24) Halder, Sunil K., et al. “Paricalcitol, a vitamin D
receptor activator, inhibits tumor formation in a
murine model of uterine fibroids.” Reproductive sciences
21.9 (2014): 1108-1119.

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.

26) Wicks, Sheila, et al. “Combinations of vitamins A,
D2 and D3 have synergistic effects in gastric and colon
cancer cells.” Functional Foods in Health and Disease
9.12 (2019): 749-771.

27) Von Essen, Marina Rode, et al. “Vitamin D controls
T cell antigen receptor signaling and activation
of human T cells.” Nature immunology 11.4 (2010):
344-349.

28) Alagbala, Adebusola A., et al. “Antitumor effects
of two less-calcemic vitamin D analogs (Paricalcitol
and QW-1624F2-2) in squamous cell carcinoma cells.”
Oncology 70.6 (2006): 483-492.

p 404
Screening for Synthetic Lethality

In 2014, Dr. V. Bhattacharjee et al. ran a
“synthetic lethal screen” on a genome-wide
siRNA library looking for gemcitabine sensitizers,
finding the vitamin D receptor (VDR)
as a top candidate. Note: Gemcitabine is the
conventional chemotherapy for pancreatic cancer,
which stalls DNA replication in cancer cells.
The added treatment with paricalcitol depletes
the VDRs (Vitamin D receptors) in cancer cells
reducing capacity for repair of chemotherapy-
induced DNA damage.

Dr. Bhattacharjee and colleagues write:

Gemcitabine sensitivity was shown to be
VDR dependent in multiple PCa [pancreatic
cancer] cell lines in clonogenic survival
assays … Thus, inhibition of VDR in PCa
cells provides a new way to enhance
the efficacy of genotoxic drugs…. We
believe that gemcitabine sensitization of
VDR-depleted cells is due to their reduced
capacity to repair damaged DNA. (18)

18) Bhattacharjee, V., Y. Zhou, and T. J. Yen. “A synthetic
lethal screen identifies the Vitamin D receptor
as a novel gemcitabine sensitizer in pancreatic cancer
cells.” Cell cycle 13.24 (2014): 3839-3856.

In 2010, Dr. Wei-dong Yu et al. studied the
effect of calcitriol (the active metabolite of vitamin
D) on a pancreatic cancer xenograft model,
finding synergy with gemcitabine with “significant
reduction in tumor volume compared to
single agent” treatment in the xenograft model.
Dr. Yu and colleagues write:

Calcitriol causes antiproliferative effects
through multiple mechanisms, including
the induction of cell cycle arrest, apoptosis
and differentiation in vitro and in vivo in
a variety of cancer cell types including
prostate, breast, colon, skin and leukemic
cells. (19)

19) Yu, Wei-Dong, et al. “Calcitriol enhances gemcitabine
antitumor activity in vitro and in vivo by promoting
apoptosis in a human pancreatic carcinoma model
system.” Cell cycle 9.15 (2010): 3094-3101.

p 404
Autophagy Upregulated in Pancreatic Cancer

Numerous studies over the years have shown
upregulated autophagy in pancreatic cancer
and inhibition of autophagy has been shown
to be beneficial in preclinical studies. (29–36)
In 2011, Dr. Shenghong Yang et al. studied
autophagy inhibitors (such as chloroquine) in
pancreatic cancer finding robust tumor regression
and prolonged survival in mouse xenograft
studies, writing:

Inhibition of autophagy by genetic
means or chloroquine treatment leads to
robust tumor regression and prolonged
survival in pancreatic cancer xenografts
and genetic mouse models. These results
suggest autophagy is actually required
for tumorigenic growth of pancreatic
cancers de novo, and drugs that inactivate
this process may have a unique clinical
utility in treating pancreatic cancers and
other malignancies with a similar dependence
on autophagy. As chloroquine and
its derivatives are potent inhibitors of
autophagy and have been used safely in
human patients for decades for a variety
of purposes, these results are immediately
translatable to the treatment of pancreatic
cancer patients, and provide a much
needed, novel vantage point of attack. (30)

30) Yang, Shenghong, et al. “Pancreatic cancers require
autophagy for tumor growth.” Genes & development
25.7 (2011): 717-729.

p 405

Pancreatic Cancer Stem Cells Increased Autophagy

In 2012, Dr. Vanessa Rausch et al. studied
autophagy in pancreatic cancer cells, finding
that hypoxia and starvation in the micro-environment
enhanced the survival of CSCs, which
had higher levels of Autophagy compared to
non-CSCs. Autophagy inhibition reduced the
migratory capacity and tumorigenicity of the
CSCs and primed them for apoptosis. Dr. Rausch
et al. write:

Our data suggest that enhanced autophagy
levels may enable survival of CSC under
H/S [hypoxia/starvation]. Interference
with autophagy-activating or -inhibiting
drugs disturbs the fine-tuned physiological
balance of enhanced autophagy in CSC
and switches survival signaling to suicide
[apoptosis]. (36)

36) Rausch, Vanessa, et al. “Autophagy mediates survival
of pancreatic tumour‐initiating cells in a hypoxic
microenvironment.” The Journal of pathology 227.3
(2012): 325-335.

The autophagy inhibitor, chloroquine has
been identified as a CSC targeting agent for
breast cancer, glioblastoma, chronic myeloid
leukemia, and pancreatic cancer. (52–53)

52) Choi, Dong Soon, et al. “Chloroquine eliminates
cancer stem cells through deregulation of Jak2 and
DNMT1.” Stem cells 32.9 (2014): 2309-2323.

53) Balic, Anamaria, et al. “Chloroquine targets pancreatic
cancer stem cells via inhibition of CXCR4 and
hedgehog signaling.” Molecular cancer therapeutics
13.7 (2014): 1758-1771.

In combination with metformin, chloroquine
eliminates CSCs in pre malignant lesions. (54)

54) Vazquez-Martin, Alejandro, et al. “Repositioning
chloroquine and metformin to eliminate cancer stem
cell traits in pre-malignant lesions.” Drug Resistance
Updates 14.4-5 (2011): 212-223

p 409
CQ or HQ has been studied in the following
cancer cell lines:

• Pancreatic cancer (86)

86) Frieboes, Hermann B., et al. “Chloroquine-Mediated
Cell Death in Metastatic Pancreatic Adenocarcinoma
Through Inhibition of Autophagy.” JOP. Journal of the
Pancreas 15.2 (2014): 189-197.

p 419
Benefits of Targeting Lysosomes

In 2016, Dr. Jessie Yanxiang Guo and Eileen
White commented that blocking V-ATPase function
in lysosomes has the added advantage of
inhibiting macropinocytosis, which is upregulated
in cancers with the K-Ras oncogene
mutation, a survival mechanism for pancreatic
cancer. Dr. Jessie Yanxiang Guo writes:

Targeting lysosomes has the added advantage
of not only blocking intracellular
protein scavenging by autophagy but also
blocking extracellular protein scavenging
by macropinocytosis. Macropinocytosis
and lysosomal degradation of albumin [and
presumably other extracellular proteins]
is an important survival mechanism for
K-Ras–driven pancreatic cancer. (24)

Note: K-Ras is an oncogene which upregulates
autophagy and micropinocytosis.

Because of their widespread clinical use and
relative safety, repurposing proton pump inhibitor
drugs as anti-cancer agents has been suggested
by a number of authors. (22–26)

22) Spugnini, Enrico Pierluigi, and Stefano Fais.
“Drug repurposing for anticancer therapies. A lesson
from proton pump inhibitors.” Expert Opinion on
Therapeutic Patents just-accepted (2020).

23) Lu, Zhen-Ning, Bing Tian, and Xiu-Li Guo.
“Repositioning of proton pump inhibitors in cancer
therapy.” Cancer chemotherapy and pharmacology
80.5 (2017): 925-937.

24) Guo, Jessie Yanxiang, and Eileen White. “Autophagy,
metabolism, and cancer.” Cold Spring Harbor symposia
on quantitative biology. Vol. 81. Cold Spring Harbor
Laboratory Press, 2016.

25) Meo-Evoli, Nathalie, et al. “V-ATPase: a master
effector of E2F1-mediated lysosomal trafficking,
mTORC1 activation and autophagy.” Oncotarget 6.29
(2015): 28057.

26) Fako, Valerie E., et al. “Repositioning proton pump
inhibitors as anticancer drugs by targeting the thioesterase
domain of human fatty acid synthase.” Journal
of medicinal chemistry 58.2 (2015): 778-784

 

p 422
PPIs studied in other cancers:
• Pancreatic cancer (38–39)

38) Tozzi, Marco, et al. “Proton Pump Inhibitors Reduce
Pancreatic Adenocarcinoma Progression by Selectively
Targeting H+, K+-ATPases in Pancreatic Cancer and
Stellate Cells.” Cancers 12.3 (2020): 640.

39) Udelnow, Andrej, et al. “Omeprazole inhibits proliferation
and modulates autophagy in pancreatic cancer
cells.” PloS one 6.5 (2011).

p 425
Loratadine/ Sulforaphane Combination

Perhaps loratadine efficacy in lung cancer
and other solid cancers would have been more
effective if combined with sulforaphane, as
reported by Dr. Desai, who studied this combination
in a pancreatic cell model, finding a
40-fold reduction in IC (inhibitory concentration)
compared to using either alone. (57)

57) Desai, Preshita, et al. “Loratadine self-microemulsifying
drug delivery systems (SMEDDS) in combination
with sulforaphane for the synergistic chemoprevention
of pancreatic cancer.” Drug delivery and translational
research 9.3 (2019): 641-651.

Sulforaphane is an OXPHOS inhibitor,
depletes prostate cancer cells of glutathione,
and is synergistic with autophagy inhibitors,
as discussed in chapter 10 on Natural
Supplements Targeting Cancer Stem Cells.

p428
3) Mukai, Shuntaro, et al. “Macrolides sensitize
EGFR-TKI-induced non-apoptotic cell death via blocking
autophagy flux in pancreatic cancer cell lines.”
International journal of oncology 48.1 (2016): 45-54.

p 430
38) Tozzi, Marco, et al. “Proton Pump Inhibitors Reduce
Pancreatic Adenocarcinoma Progression by Selectively
Targeting H+, K+-ATPases in Pancreatic Cancer and
Stellate Cells.” Cancers 12.3 (2020): 640.

 

p 437

TQ Effective for Cancer Cell Lines
• Pancreatic cancer (73)

73) Relles, Daniel, et al. “Thymoquinone promotes
pancreatic cancer cell death and reduction of tumor
size through combined inhibition of histone deacetylation
and induction of histone acetylation.” Advances
in preventive medicine 2016 (2016).

p 451
Autophagy Induced by Tyrosine Kinase Inhibitors

In 2020, Dr. Hideki Tanaka et al. studied
autophagy induced by various tyrosine kinase
inhibitors, and their enhanced cytotoxicity via
inhibition of autophagy with azithromycin.
One of the more potent growth stimulators
for the cancer cell is endothelial growth
factor receptor (EGFR), located on the outer
membrane of cancer cells. EGFR is a tyrosine
kinase receptor that activates the PI3K-AKTmTOR
pathway, which potently inhibits autophagy.
Blocking this EGFR receptor with an
EGFR-TKI drug such as gefitinib (GEF) or erlotinib
potently induces “protective autophagy.”
Macrolide antibiotics, azithromycin (AZM), and
clarithromycin strongly inhibit autophagy flux
and enhanced the cytotoxicity of EGFR-TKIs
in non-small-cell lung cancer and pancreatic
cancer, resulting in “non-apoptotic cell death.”
Azithromycin showed the most potent effect.
Dr. Tanaka et al. write:

The multi-kinase inhibitors appear to have a
higher propensity for autophagy induction.
Once autophagy was induced, blocking
TKI-induced autophagy with AZM resulted
in enhanced cytotoxicity via non-apoptotic
cell death. These data suggested a clinical
benefit in cancer therapy for the combination
therapy of TKI and AZM. (38–39)

38) Tanaka, Hideki, et al. “Comparison of autophagy
inducibility in various tyrosine kinase inhibitors and
their enhanced cytotoxicity via inhibition of autophagy
in cancer cells in combined treatment with azithromycin.”
Biochemistry and Biophysics Reports 22
(2020): 100750.

39) 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 456
Many Successful Clinical Trials

One of the attractive features of itraconazole
is that the drug has been the subject of numerous
successful clinical trials, showing clinical
benefit in prostate and basal cell carcinoma,
as well as survival advantage with the itraconazole/
chemotherapy combination for relapsed
non‑small-cell lung, ovarian, triple-negative
breast, pancreatic, and biliary-tract cancer.(5)

5) Tsubamoto, Hiroshi, et al. “Repurposing itraconazole
as an anticancer agent.” Oncology Letters 14.2
(2017): 1240-1246.

p 457
Itraconazole Clinical Trials

As mentioned above, there are many ongoing
clinical trials using Itraconazole for prostate,
gastric, pancreatic, esophageal, lung,
gynecologic, and basal cell cancers.

p 477
Fenofibrate Inhibits Fatty Acid
Synthetase – Hepatoma Model

In 2019, Dr. Bang-Jau You et al. studied the
effect of fenofibrate on hepatoma cells (liver
cancer) in vitro, a cancer with highly expressed
fatty acid synthetase (FASN) involved in generating
fatty acids for tumor energy requirements.
Dr. You and colleagues found that fenofibrate
docked into the binding site of FASN, blocking
its activity, in an effect similar to that of orlistat,
an FDA-approved drug for treatment of obesity.
By blocking FASN, fenofibrate produced
a potent anti-cancer effect, causing apoptosis
and necroptosis in a human hepatoma model
in vitro. (25)

25) You, Bang-Jau, et al. “Fenofibrate induces human
hepatoma Hep3B cells apoptosis and necroptosis
through inhibition of thioesterase domain of fatty acid
synthase.” Scientific reports 9.1 (2019): 3306.

 

p 477
Fenofibrate Synergy with Taxanes

FASN is also involved with production of
palmitate, a component in construction of
microtubules, so FASN inhibition leads to
microtubule disruption in the cancer cells. In
2017, Dr. Timothy Heuer et al. studied combining
FASN inhibitors with a taxane, paclitaxel, or
with docetaxel, a microtubule inhibitor chemotherapy
agent, to enhance anti-cancer activity
in xenograft models of lung, ovarian, prostate,
and pancreatic cancer. Indeed, highly proliferating,
invasive cancer cell types are addicted to
FASN to maintain lipid rafts, microtubules, and
other lipid functions in the cancer cell. FASN
inhibition causes:

1) blockade of palmitate synthesis
2) disruption of membrane-associated protein,
localization and plasma membrane architecture,
3) inhibition of oncogenic signal transduction
[e.g. Wnt-β-catenin and Akt],
4) gene expression reprogramming.
5) induction of tumor cell apoptosis. (34)

34) Heuer, Timothy S., et al. “FASN inhibition and taxane
treatment combine to enhance anti-tumor efficacy
in diverse xenograft tumor models through disruption
of tubulin palmitoylation and microtubule organization
and FASN inhibition-mediated effects on oncogenic
signaling and gene expression.” EBioMedicine
16 (2017): 51-62.

The studies by Dr. Heuer’s group found
enhanced synergy both in vitro and in vivo
when FASN inhibitors (TVB-3166 and 3664)
were combined with taxane drugs. Dr. Heuer
et al. write that the combination of FASN inhibition
and a taxane drug:

demonstrate significantly enhanced
anti-tumor efficacy when FASN inhibition
is combined with paclitaxel or docetaxel
in vitro and in vivo … Impressively, the
effects include induction of near complete
tumor regression in a variety of diverse
tumor cell-line-and patient-derived tumor
models that include lung, ovarian, pancreatic,
and prostate tumor models …
Together, these results provide compelling
mechanism- and efficacy-based evidence
for combined FASN and taxane therapy as
a cancer therapy. (34)

34) Heuer, Timothy S., et al. “FASN inhibition and taxane
treatment combine to enhance anti-tumor efficacy
in diverse xenograft tumor models through disruption
of tubulin palmitoylation and microtubule organization
and FASN inhibition-mediated effects on oncogenic
signaling and gene expression.” EBioMedicine
16 (2017): 51-62.

Once might speculate on taxane synergy
with other FASN inhibitors, such as orlistat,
fenofibrate and quercetin. (99)

99) Sultan, Ahmed S., et al. “Quercetin induces apoptosis
in triple-negative breast cancer cells via inhibiting
fatty acid synthase and β-catenin.” Int. J. Clin. Exp.
Pathol 10.1 (2017): 156-172.

One might also speculate on synergy of fenofibrate
with microtubule-disrupting agents,
mebendazole, and fenbendazole. We await
confirmation with NIH-funded studies of these
combinations.

p 496
Celecoxib Studied in Various
Cancer Cell Types
• Pancreatic cancer (122)(159)

122) Qiu, Xiaoxin, et al. “S-1 and celecoxib synergistically
suppress pancreatic cancer growth by promoting
apoptosis in vivo and in vitro.” Int J Clin Exp Med 12.4
(2019): 3201-3213.

159) Zuo, Chaohui, et al. “Celecoxib suppresses proliferation
and metastasis of pancreatic cancer cells by
down-regulating STAT3/NF-kB and L1CAM activities.”
Pancreatology 18.3 (2018): 328-333.

 

p 511
4) He, Tian-Lin, et al. “The c-Myc–LDHA axis positively
regulates aerobic glycolysis and promotes tumor progression
in pancreatic cancer.” Medical Oncology 32.7
(2015): 187

p 519
Dipyridamole prevents metastasis in these
cancer cell models:
• Pancreatic cancer with metastasis to
liver (35)

p 527
35) Tzanakakis, George N., Kailash C. Agarwal, and
Michael P. Vezeridis. “Prevention of human pancreatic
cancer cell‐induced hepatic metastasis in nude mice
by dipyridamole and its analog RA‐233.” Cancer 71.8
(1993): 2466-2471.

 

p 530

106) Brandi, Jessica, et al. “Proteomic analysis of pancreatic
cancer stem cells: Functional role of fatty acid
synthesis and mevalonate pathways.” Journal of proteomics
150 (2017): 310-322.

p 533
156) Sadighara, Melina, et al. “Protective effects of
coenzyme Q10 and L-carnitine against statin-induced
pancreatic mitochondrial toxicity in rats.” Research in
Pharmaceutical Sciences 12.6 (2017): 434.

 

Chapter 41 Tocotrienol Vitamin E

p 534
In vivo and in vitro studies using gamma-
tocotrienol have shown anticancer activity
against leukemia, breast, colon, prostate, pancreatic
and lung cancers. In-vivo studies have
shown suppression of angiogenesis, suppression
of metastasis, and targeting of CSCs (5-9)

4) Springett, Gregory M., et al. “A phase I safety,
pharmacokinetic, and Pharmacodynamic Presurgical
trial of vitamin E δ-tocotrienol in patients with pancreatic
ductal neoplasia.” EBioMedicine 2.12 (2015):
1987-1995.

p 535
Pancreatic Cancer
In 2017, Dr. Husain studied Delta-Tocotrienol
in a transgenic mouse model of PDAC (pancreatic
ductal carcinoma) finding inhibition of cancer
cell migration, invasion, EMT, angiogenesis,
and inhibition of CSCs. (13)

13) Husain, Kazim, et al. “δ-Tocotrienol, a natural
form of vitamin E, inhibits pancreatic cancer stemlike
cells and prevents pancreatic cancer metastasis.”
Oncotarget 8.19 (2017): 31554.

p 535
Anti-Cancer Efficacy of Tocotrienol
has been found in preclinical studies
in various cancer cell types:

• Pancreatic Cancer (13) (33)

13) Husain, Kazim, et al. “δ-Tocotrienol, a natural
form of vitamin E, inhibits pancreatic cancer stemlike
cells and prevents pancreatic cancer metastasis.”
Oncotarget 8.19 (2017): 31554.

33) Palau, Victoria E., et al. “γ-Tocotrienol induces
apoptosis in pancreatic cancer cells by upregulation
of ceramide synthesis and modulation of sphingolipid
transport.” BMC cancer 18.1 (2018): 1-14.

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 177
116) Zagon, Ian S., and Patricia J. McLaughlin. “Opioid
growth factor and the treatment of human pancreatic cancer:
a review.” World Journal of Gastroenterology: WJG 20.9 (2014): 2218.

================ END ====================

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