Index for Colon Cancer

Index for Colon Cancer for Cracking Cancer Toolkit

by Jeffrey Dach MD


Zhou, Shican, et al. “Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth.” Frontiers in Pharmacology (2021): 2145.

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

Dueñas-González, Alfonso, and Mandy Juárez-Rodríguez. “Ivermectin: Potential Repurposing of a Versatile Antiparasitic as a Novel Anticancer.” Repurposed Drugs for Cancer. IntechOpen, 2021.

Tang, Mingyang, et al. “Ivermectin, a potential anticancer drug derived from an antiparasitic drug.” Pharmacological Research 163 (2021): 105207.

Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase.

Lee, Da Eun, et al. “Ivermectin and gemcitabine combination treatment induces apoptosis of pancreatic cancer cells via mitochondrial dysfunction.” Frontiers in Pharmacology (2022): 3403.

Ma, Shu‐Chang, et al. “Novel strategies to reverse chemoresistance in colorectal cancer.” Cancer Medicine (2023).


P 38
24) Apostolou, Panagiotis, et al. “P-280 The molecular
profile of colon cancer cells.” Annals of Oncology 28.
suppl 3 (2017).

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.

29) Toloudi, Maria, et al. “A possible clinical benefit of
the identification and characterization of colon cancer
stem cells.” Asian Pacific Journal of Tropical Disease
5.1 (2015): 22-27.

p 45

25) Qiao, Chen, et al. “UCP2‐related mitochondrial
pathway participates in oroxylin A‐induced apoptosis
in human colon cancer cells.” Journal of cellular physiology


p. 50
Similar induction of “protective autophagy” occurred
in cancer cells after DCA treatment in esophageal
cancer and colon cancer in vitro. (29–30)


29) Jia, Hong‑Yu, et al. “Dichloroacetate induces protective
autophagy in esophageal squamous carcinoma
cells.” Oncology letters 14.3 (2017): 2765-2770.

30) Gong, F., et al. “Dichloroacetate induces protective
autophagy in LoVo cells: involvement of cathepsin D/
thioredoxin-like protein 1 and Akt-mTOR-mediated signaling.”
Cell death & disease 4.11 (2013): e913-e913.five colorectal cancer cell lines (LoVo,SW620, HCT116, SW480 and LS174t)

150) Lin, G., et al. “Dichloroacetate induces autophagy
in colorectal cancer cells and tumours.” British journal
of cancer 111.2 (2014): 375-385.

p 63

10) Khan, Akbar, Douglas Andrews, and Anneke C.
Blackburn. “Long-term stabilization of stage 4 colon
cancer using sodium dichloroacetate therapy.” World
journal of clinical cases 4.10 (2016): 336.

p 68.

106) Aono, Yuichi, et al. “Sulindac sulfone inhibits
the mTORC1 pathway in colon cancer cells by directly
targeting voltage-dependent anion channel 1 and 2.”
Biochemical and biophysical research communications
505.4 (2018): 1203-1210.

Beta Blockers

p 75

Additional studies describe
beta blockers conferring similar reduction in
cancer mortality in prostate cancer, melanoma,
colon, ovarian, prostate, non-small-cell lung,
and hepatocellular, multiple myeloma. (37)


37) Barron, Thomas I., et al. “Beta blockers and breast
cancer mortality: a population-based study.” J Clin
Oncol 29.19 (2011): 2635-2644.


p 79

Population Study Beta Blockers Reduce Cancer

In 2015, Dr. Pig Ying Chang et al. reviewed
a database of 24,238 patients over a 12-year
follow-up. Dr. Chang’s group report:
Patients with propranolol treatment exhibited
significantly lower risks of cancers in
head and neck (HR: 0.58), esophagus (HR:
0.35), stomach (HR: 0.54), colon (HR: 0.68),
and prostate cancers (HR: 0.52). [HR=
Hazard Ratio]. (33)

33) Chang, Ping-Ying, et al. “Propranolol reduces
Cancer risk: a population-based cohort study.”
Medicine 94.27 (2015).

p 87 Alpha Lipoic Acid ALA

In 2019, Dr. Ivana Damnjanovic studied
alpha lipoic acid (ALA) in a human colon cancer
cell line, finding inhibition of the anti-apoptotic
protein BCL-2 and activation of the pro-apoptotic
BAX protein. This finding suggests that
ALA is a BH3 mimetic similar to the new FDAapproved
drug, venetoclax (ABT-199), a selective
BCL-2 inhibitor. (7)

7) Damnjanovic, Ivana, et al. “Possible molecular
mechanisms and pathways involved in BH3 mimetic
activity of alpha-lipoic acid on human colon cancer
cell line.” Farmacia (2019).

p 88

Dr. U. Wenzel et al. studied the effect of ALA
on colon cancer cells, finding:
ALA was able to increase Oxygen generation
inside mitochondria. Increased mitochondrial
O2 production was preceded by
an increased influx of lactate or pyruvate
into mitochondria, and resulted in the
downregulation of the anti-apoptotic protein
BCL-2…. In contrast to HT-29 [colon
cancer] cells, no apoptosis was observed
in non-transformed human colonocytes
[normal cells] in response to ALA. (11)


11) Wenzel, U., A. Nickel, and H. Daniel. “Alpha-lipoic
acid induces apoptosis in human colon cancer cells by
increasing mitochondrial respiration with a concomitant
O2 generation.” Apoptosis 10.2 (2005): 359-368.


p 94 Melatonin

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)

62) Reiter, Russel J., et al. “Inhibition of mitochondrial
pyruvate dehydrogenase kinase: a proposed mechanism
by which melatonin causes cancer cells to overcome
cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy.” Melatonin
Research 2.3 (2019): 105-119.

63) Reiter, Russel J., et al. “Melatonin, a full service
anti-cancer agent: inhibition of initiation, progression
and metastasis.” International journal of molecular sciences
18.4 (2017): 843.

64) Reiter, Russel J., Dun Xian Tan, and Annia Galano.
“Melatonin: exceeding expectations.” Physiology 29.5
(2014): 325-333.


p 100

37) J Nutr. 2005 Jun; 135(6):1510-4. Increased carnitine-
dependent fatty acid uptake into mitochondria of
human colon cancer cells induces apoptosis. Wenzel
U1, Nickel A, Daniel H.

p 102

77) Lee, Jun Hee, et al. “Melatonin and 5‐fluorouracil
co‐suppress colon cancer stem cells by regulating
cellular prion protein‐Oct4 axis.” Journal of pineal
research 65.4 (2018): e12519.


p 102

81) Gao, Yue, et al. “Melatonin synergizes the chemotherapeutic
effect of 5‐fluorouracil in colon cancer by
suppressing PI 3K/AKT and NF‐κB/iNOS signaling pathways.”
Journal of pineal research 62.2 (2017): e12380


105) Kawakita, Hideaki, et al. “Growth inhibitory
effects of vitamin K2 on colon cancer cell lines via
different types of cell death including autophagy and
apoptosis.” International journal of molecular medicine
23.6 (2009): 709-716.

p 121

In- Situ (Intracrine) Aromatase Activity in Colon Cancer

One does not usually associate estrogen production
with colonic epithelium or colon cancer
cells. However, Dr. Sato et al. in 2012 found
that “colon carcinoma expresses functional aromatase,
and that estrogens are locally synthesized
in the tumor tissues.”(25)


25) Sato, Ryuichiro, et al. “Aromatase in colon carcinoma.”
Anticancer research 32.8 (2012): 3069-3075.

p 121

More Drug Combinations

A combination that includes all or some
of the following: exemestane, doxycycline,
itraconazole, fenofibrate, clarithromycin, simvastatin,
metformin, etc. might be suggested
for breast cancer patients, along with weekly
intravenous high-dose vitamin C. Other aromatase-
producing cancer-cell types (colon,
lung, skin etc.) might also benefit from such
a combination of drugs that block molecular
pathways in cancer cells.

p 123

Doxycycline Synergy with Celecoxib in Colon Cancer

In 2006, Dr. Toshinao Onoda reported that
doxycycline induces apoptosis via the mitochondrial
pathways in colon cancer cells (in
vitro), finding the combination of doxycycline
and COX-2 inhibitor (celecoxib) synergistic.

43) Onoda, Toshinao, et al. “Tetracycline analogues
(doxycycline and COL‐3) induce caspase‐dependent
and‐independent apoptosis in human colon cancer
cells.” International Journal of Cancer 118.5 (2006):
44) Onoda, Toshinao, et al. “Doxycycline inhibits cell
proliferation and invasive potential: combination therapy
with cyclooxygenase-2 inhibitor in human colorectal
cancer cells.” Journal of Laboratory and Clinical
Medicine 143.4 (2004): 207-216.

p 138 Sulforaphane

Similarly, in 2010, Dr. Nishikawa found that
the addition of autophagy inhibitor “potentiated
sulforaphane-induced apoptosis” in a
colon cancer model. (89)

89) Nishikawa, Takeshi, et al. “Inhibition of autophagy
potentiates sulforaphane-induced apoptosis in human
colon cancer cells.” Annals of Surgical Oncology 17.2
(2010): 592-602.

p 142 Curcumin

9) Mbese, Zintle, Vuyolwethu Khwaza, and Blessing
Atim Aderibigbe. “Curcumin and Its Derivatives as
Potential Therapeutic Agents in Prostate, Colon and
Breast Cancers.” Molecules 24.23 (2019): 4386.

p 143

20) Langner, Ewa, Marta Kinga Lemieszek, and
Wojciech Rzeski. “Lycopene, sulforaphane, quercetin,
and curcumin applied together show improved antiproliferative
potential in colon cancer cells in vitro.”
Journal of food biochemistry 43.4 (2019): e12802.

p 144

49) Ruan, H., et al. “Berberine binds RXRα to suppress
β-catenin signaling in colon cancer cells.” Oncogene
36.50 (2017): 6906-6918.

p 159

ATRA Markedly Augments Anti-Tumor Immunity

In 2019, Dr. Lu Huang et al. studied ATRA
in lung cancer and colon cancer mouse xenografts,
finding ATRA markedly upregulated
anti-tumor immunity. Dr. Huang’s group write:
Flow cytometry assays conducted on
intratumoral immune cells revealed that
ATRA-treatment decreased the CD8+ T to
T-reg cellular ratios while increasing the
ratios of CD8+ T to T-reg cells… Taken
together, this study uncovered a previously
unrecognized role for ATRA in augmenting
immunotherapy. These preclinical immunotherapy
findings can be translated into the
cancer clinic. (104)

p 172 pyrvinium

21) Wiegering, Armin, et al. “The impact of pyrvinium
pamoate on colon cancer cell viability.” International
journal of colorectal disease 29.10 (2014): 1189-1198.

p 170 Pyrvinium for Colonic Polyposis

In 2014, Dr. Bin Li et al. suggested pyrvinium
as a Wnt-inhibitor treatment for FAP (familial
adenomatous polyposis), which is driven by
mutations that upregulate the Wnt pathway
and frequently result in colorectal cancer. They
We show that Pyrvinium can function as
an in vivo inhibitor of Wnt-signaling and
polyposis in a mouse model of FAP: APCmin
mice [familial polyposis]…. Oral administration
of Pyrvinium, a CK1α agonist, attenuated
the levels of Wnt -driven biomarkers
and inhibited adenoma formation in
APCmin mice. Considering its well-documented
safe use for treating enterobiasis
in humans, our findings suggest that
Pyrvinium could be repurposed for the clinical
treatment of Adenomatous Polyposis
Coli APC-associated polyposes. (20)

20) Li, Bin, et al. “Repurposing the FDA-approved pinworm
drug pyrvinium as a novel chemotherapeutic
agent for intestinal polyposis.” PLoS One 9.7 (2014).

p 176

Aspirin after Colorectal Surgery Reduces Mortality

In 2019, Dr. Joseph Sung et al. studied aspirin
use after colorectal surgery by 13,528
patients followed over 10 years and found a
31% reduction in colon cancer mortality in
continuous aspirin users and a 39% reduction
in all-cause mortality. (9)


9) Sung, Joseph JY, et al. “Low‐dose aspirin can reduce
colorectal cancer mortality after surgery: A 10‐year follow‐
up of 13 528 colorectal cancer patients.” Journal
of gastroenterology and hepatology 34.6 (2019):


p 177

Overcoming Chemotherapy Resistance
by Preventing NF-kB Activation

In 2019, Dr. Jonbo Fu et al. found that aspirin
overcomes 5-FU chemotherapy resistance
in a colorectal cancer cell model by preventing
chemotherapy-induced NF-kB activation. (21)
This finding was confirmed in 2020 by
Dr. Wei Jiang et al., also in a colon cancer cell
model, finding that aspirin prevented binding
of NF-kB to the COX-2 promoter. (22)

21) Fu, Jinbo, et al. “Aspirin suppresses chemoresistance
and enhances antitumor activity of 5-Fu
in 5-Fu-resistant colorectal cancer by abolishing
5-Fu-induced NF-κB activation.” Scientific reports 9.1
(2019): 1-11.

22) Jiang, Wei, et al. “Aspirin enhances the sensitivity
of colon cancer cells to cisplatin by abrogating
the binding of NF-κB to the COX-2 promoter.” Aging
(Albany NY) 12.1 (2020): 611.


p 200 Metformin

Metformin, through activation of the
AMPK pathway, produces a dose-dependent
increase in tumor glucose uptake
while decreasing cell proliferation in human
and murine colon cancer cells. (88)

88) Habibollahi, Peiman, et al. “Metformin—an adjunct
antineoplastic therapy—divergently modulates tumor
metabolism and proliferation, interfering with early
response prediction by 18F-FDG PET imaging.” Journal
of Nuclear Medicine 54.2 (2013): 252-258.

p 214 Pterostilbene

Studies have confirmed that pterostilbene
exerts antiproliferative and pro-apoptotic
effects in various cancer cell types, including
lung, gastric, prostate, colon, breast cancers,
chronic myelogenous leukemia, and lymphoblastic
leukemia and is useful for anti-aging and
neuroprotection. (4–7)(11–18)

4) Nutakul, Wasamon, et al. “Inhibitory effects of resveratrol
and pterostilbene on human colon cancer
cells: a side-by-side comparison.” Journal of agricultural
and food chemistry 59.20 (2011): 10964-10970.

p 215

Autophagy Flux Inhibitor—
Lysosomal Membrane Disruption
In 2012, Dr. Salvador Mena et al. studied the
mechanism of action (MOA) of pterostilbene
anti-cancer activity in various cancer cell types
with melanoma and lung the most susceptible,
and colon and breast most resistant due
to the level of heat shock protein.

40) Lai, Ching-Shu, et al. “3′-Hydroxypterostilbene
Suppresses Colitis-Associated Tumorigenesis by
Inhibition of IL-6/STAT3 Signaling in Mice.” Journal
of agricultural and food chemistry 65.44 (2017):

41) Tolba, Mai F., and Sherif Z. Abdel-Rahman.
“Pterostilbine, an active component of blueberries,
sensitizes colon cancer cells to 5-fluorouracil cytotoxicity.”
Scientific reports 5 (2015): 15239.

42) Cheng, Tzu-Chun, et al. “Potent anti-cancer effect
of 3′-hydroxypterostilbene in human colon xenograft
tumors.” PLoS One 9.11 (2014): e111814.

43) Chiou, Yi-Siou, et al. “Pterostilbene inhibits colorectal
aberrant crypt foci (ACF) and colon carcinogenesis
via suppression of multiple signal transduction pathways
in azoxymethane-treated mice.” Journal of agricultural
and food chemistry 58.15 (2010): 8833-8841.

p 217

Dr. Shiby Paul et al. (2010) write:
Pterostilbene downregulated the expression
of Beta-Catenin and cyclin D1 targets
of Wnt pathway…. .pterostilbene reduced
the Wnt agonist-induced levels of cyclin D1
and Beta-Catenin in the nucleus … pterostilbene
inhibits colon tumorigenesis by
regulating the Wnt/Beta-Catenin-signaling
pathway and the inflammatory responses.

44) Paul, Shiby, et al. “Dietary intake of pterostilbene, a
constituent of blueberries, inhibits the β-catenin/p65
downstream signaling pathway and colon carcinogenesis
in rats.” Carcinogenesis 31.7 (2010): 1272-1278

p 230 Boswellia

55) Wang, Dan, et al. “Boswellic acid exerts potent
anticancer effects in HCT-116 human colon cancer cells
mediated via induction of apoptosis, cell cycle arrest,
cell migration inhibition and inhibition of PI3K/AKT signalling
pathway.” J. BUON 23.2 (2018): 340-345.


p 231 Solomons Seal

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 Warburgtype
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)

p 232

FDA-Approved Anti-EGF Monoclonal Antibodies

Cetuximab and panitumumab are anti-EGFR
monoclonal antibodies, new oncology drugs
used for head and neck cancer and metastatic
colon cancer.

Solomon’s seal is a natural EGFR inhibitor for
cancer cell types with hyperactive EGFR. Like
many other anti-cancer drugs, PCL (Solomon’s
seal) induces protective autophagy by downregulating
the mTOR pathway.

p 246

Cryptosporidium Mouse Model of Colon Cancer

Another animal model of parasitic disease
inducing cancer is found in the laboratory of
Dr. Sadia Benamrouz et al. (2014) who reported
that mice inoculated with the Cryptosporidium
parasite quite unexpectedly develop colon cancer.
Dr. Benamrouz found histochemical evidence
of upregulated Wnt signaling pathways,
commonly upregulated in cancer cells. (22)

22) Benamrouz, Sadia, et al. “Cryptosporidium parvum-
induced ileo-caecal adenocarcinoma and Wnt
signaling in a mouse model.” Disease Models and
Mechanisms 7.6 (2014): 693-700.

p 248 Niclosamide

In 2011, Dr. Takuya Osada et al. reported
in Cancer Research that orally administered
niclosamide is well tolerated, with oral doses
achieving therapeutic plasma levels associated
with biologic activity, leading to tumor control:
We found that niclosamide inhibited Wnt/β-
catenin pathway activation, downregulated
Dvl2, decreased downstream β-catenin
signaling, and exerted antiproliferative
effects in human colon cancer cell lines and
CRC [Colorectal Cancer] cells isolated by
surgical resection of metastatic disease,
regardless of mutations in APC…. . In mice
implanted with human CRC xenografts,
orally administered niclosamide was well
tolerated, achieved plasma and tumor
levels associated with biologic activity,
and led to tumor control. Our findings
support clinical explorations to reposition
niclosamide for the treatment of CRC. (46)

46) Osada, Takuya, et al. “Antihelminth compound
niclosamide downregulates Wnt signaling and elicits
antitumor responses in tumors with activating APC
mutations.” Cancer research 71.12 (2011): 4172-4182.


p 248

In 2019, Dr. So-Yeon Park et al. found
niclosamide effective against colorectal cancer
cell lines in vitro and in vivo xenografts, and
sensitized colon cancer to chemotherapy and
radiotherapy, writing:
We revealed that niclosamide exerts in
vivo effects against both colon carcinogenesis
and tumor growth by targeting
the Wnt/LEF1/DCLK1-B axis-mediated CSC
[Cancer Stem Cell] properties. Niclosamide
inhibits certain CSC functions including
survival, anti-apoptosis, and self-renewal,
resulting in a reduction in CSC populations.
Moreover, CSC-targeting niclosamide
successfully sensitizes colorectal cancer to
chemo-radiation. (49)


49) Park, So-Yeon, et al. “Inhibition of LEF1-mediated
DCLK1 by niclosamide attenuates colorectal cancer
stemness.” Clinical Cancer Research 25.4 (2019):

Another similar “azole” family drug, flubendazole,
has anti-cancer activity, inducing
mitotic catastrophe in colon cancer and melanoma
cells. (95–96)

95) Králová, Věra, et al. “Flubendazole induces mitotic
catastrophe and senescence in colon cancer cells in
vitro.” Journal of Pharmacy and Pharmacology 68.2
(2016): 208-218.

96) Čáňová, K., et al. “Flubendazole induces mitotic
catastrophe and apoptosis in melanoma cells.”
Toxicology in Vitro 46 (2018): 313-322.

p 257 Mebendazole

79) Nygren, Peter, and Rolf Larsson. “Drug repositioning
from bench to bedside: Tumour remission by the
antihelmintic drug mebendazole in refractory metastatic
colon cancer.” Acta Oncologica 53.3 (2014):


p 259 Artemisinin Prospective Randomized Trial in Colon Cancer

After the operation, it seemed the cancer
was gone. However, Susan was worried about
recurrence, which can happen because microscopic
cancer cells may have already spread
outside the colon. While reading the newspaper,
Susan saw a news story about Dorothy B., a
colon cancer patient who participated in a clinical
study with Dr. Sanjeev Krishna at St George
University London in 2010. (1–2)

This 2015 randomized study by Dr. Sanjeev
Krishna et al. included 20 colon cancer patients
awaiting “curative resection” for colon cancer.
(1–2) Half received the artesunate pill for two
weeks prior to surgery, and the other half a
placebo. Five years later, there were 6 cancer
recurrences in the placebo group, but only one
in the artesunate (artemisinin) group. There
were no deaths in the artesunate group, compared
to three deaths in the placebo group. I
was very impressed by this.

1) Krishna, Sanjeev, et al. “A randomised, double blind,
placebo-controlled pilot study of oral artesunate therapy
for colorectal cancer.” EBioMedicine 2.1 (2015):
2) Augustin, Yolanda, et al. “The wisdom of crowds and
the repurposing of artesunate as an anticancer drug.”
ecancermedicalscience 9 (2015).

p 265 Butyrate

In a 2013 report, Dr. Jane Fauser studied
the anti-cancer effects of butyrate and coconut
oil (lauric acid) on a colon cancer cell line. Dr.
Fauser reported butyrate induces apoptosis by
inhibiting histone deacetylase activity,
inducing cell cycle arrest, promoting differentiation,
activating NF-κB, downregulating
α 2 β 1 , modifying glucose availability,
and inducing caspase activation in colon
cancer cell. (46)

46) Fauser, Jane Kathryn. Medium Chain Fatty Acids
and Wnt/β-Catenin Inhibitors as Adjunctive Colorectal
Cancer Chemotherapeutic Agents. Diss. The University
of Adelaide, 2012

p 272 Ivermectin

In 2014, Dr. Melotti et al. studied ivermectin
in a colon cancer cell model, finding it effective
at micromolar concentrations against
both tumor bulk as well as cancer stem cells.
The authors suggested that ivermectin might
be useful as a routine prophylactic agent—for
instance, against colon cancer in familial polyposis
or to prevent nascent cancer in the general
aging population. (111)

111) Melotti, Alice, et al. “The river blindness drug
Ivermectin and related macrocyclic lactones inhibit
WNT‐TCF pathway responses in human cancer.” EMBO
molecular medicine (2014): e201404084.

p 142 Artesunate

142) Jiang, Feng, et al. “Artesunate induces apoptosis
and autophagy in HCT116 colon cancer cells, and
autophagy inhibition enhances the artesunate‑induced
apoptosis.” International journal of molecular
medicine 42.3 (2018): 1295-1304.

p 299

Mitochondrial Uncoupling for Colon Cancer

Dr. Amer Alasadi et al. (2018) studied the
effect of mitochondrial uncoupler niclosamide
on hepatic metastasis in colon cancer. Dr.
Alasadi ‘s group writes:

Dr. Alasadi’s study used niclosamide in cultured
colon cancer cells, and colon cancer xenografts
showed that mitochondrial uncoupling:
promotes pyruvate influx to mitochondria
and reduces various anabolic pathway
activities, inhibits cell proliferation
and reduces clonogenicity of cultured
colon cancer cells. Furthermore, oral
treatment with mitochondrial uncoupler
[niclosamide] reduces intestinal polyp
formation in APCmin/+ mice [genetically
modified mice having familial polyposis of
the colon], and diminishes hepatic metastasis
of colon cancer cells transplanted
intrasplenically. (23)

The use of niclosamide for colon cancer has
been extensively studied. The mechanism of
action, as described by Dr. Mohammed Suliman
et al. in 2016, is downregulation of Notch pathway
and upregulation of tumor suppressor
gene miR-200. (24)

Downregulating the Wnt Pathway
Perhaps, the highest level of interest is
devoted to niclosamide’s ability to downregulate
the Wnt/Beta-Catenin signaling pathway, a
pathway activated by mutations in colonic polyps
in 80% of colon cancer cases. (25)

In 2011, Dr. Takuya Osada et al. found:
In mice implanted with human CRC
[ColoRectal Cancer] xenografts, orally
administered niclosamide was well tolerated,
achieved plasma and tumor levels

associated with biologic activity, and led to
tumor control. Our findings support clinical
explorations to reposition niclosamide for
the treatment of CRC. (26)

Potent Wnt Inhibitor
In 2019, Dr. So-Yeon Park et al. investigated
the molecular mechanism by which niclosamide
is a potent Wnt inhibitor and anti-cancer stem
cell agent in colon cancer. Dr. Park’s study concluded
that niclosamide
exerts in vivo effects against both colon
carcinogenesis and tumor growth by
targeting the Wnt/LEF1/DCLK1-B axis-mediated
CSC [cancer stem cell] properties.
Niclosamide inhibits certain CSC functions
including survival, anti-apoptosis, and
self-renewal, resulting in a reduction in
CSC populations. Moreover, CSC-targeting
niclosamide successfully sensitizes colorectal
cancer to chemo-radiation. These
findings provide a preclinical rationale
to broaden the clinical evaluation of
niclosamide for colorectal cancer treatment.


Wnt/Β-catenin/S100A4 Pathway
The downstream signaling protein induced
by Wnt pathway activation at the cell membrane
is Beta-Catenin, which then localizes to
the nucleus and activates transcription of the
S100A4 gene and protein. This is the subject
of a 2016 study by Dr. Mathias Dahlman et al.,
finding that elevated levels of S100A4 protein
predicted metastatic behavior with poor prognosis
in mouse xenograft studies, as well as in
human colon cancer cases. (28)

Dr. Susen Burock’s group performed a
high-throughput screen identifying niclosamide
as an inhibitor of S100A4 gene expression. (29)
Niclosamide Human Clinical Trials
In view of the above excellent results with
in vitro and in vivo studies, two human clinical
trials of niclosamide in colon cancer are underway.
The first is sponsored by Michael A Morse,
MD, at Duke University, a phase 1 study of 18
patients given niclosamide for 7 days prior to
surgical resection of their colon cancer (clinical
trial NCT02687009). The study completion
date is July 2022.
The second is a phase 2 trial led by Dr.
Burock in Charite University, Berlin, Germany
(NCT02519582) in which 37 patients with progressive
metastatic colon cancer are treated
with oral niclosamide (2 grams daily) until
disease progression or unacceptable toxicity.
Measurement of S100A4 protein levels will be
done (see Dr. Mathias Dahlman et al. above); the
estimated study completion date was August
2020. (As of this writing, no results have been
posted.) I would assume the 2 gram per day
dosage was chosen because it is the same dosage
for dwarf hookworm, and provides serum
concentrations of 0.25–6.0 micrograms per milliliter,
corresponding with effective anti-cancer
activity in many of the in vitro and in vivo studies.


23) Alasadi, Amer, et al. “Effect of mitochondrial
uncouplers niclosamide ethanolamine (NEN) and oxyclozanide
on hepatic metastasis of colon cancer.” Cell
death & disease 9.2 (2018): 215.

24) Suliman, Mohammed A., et al. “Niclosamide inhibits
colon cancer progression through downregulation
of the Notch pathway and upregulation of the tumor
suppressor miR-200 family.” International journal of
molecular medicine 38.3 (2016): 776-784.

25) Monin, Malte B., et al. “The anthelmintic
niclosamide inhibits colorectal cancer cell lines via
modulation of the canonical and noncanonical Wnt
signaling pathway.” Journal of Surgical Research 203.1
(2016): 193-205.

26) Osada, Takuya, et al. “Antihelminth compound
niclosamide downregulates Wnt signaling and elicits
antitumor responses in tumors with activating APC
mutations.” Cancer research 71.12 (2011): 4172-4182.

27) Park, So-Yeon, et al. “Inhibition of LEF1-mediated
DCLK1 by niclosamide attenuates colorectal cancer
stemness.” Clinical Cancer Research 25.4 (2019):

28) Dahlmann, Mathias, et al. “S100A4 in cancer
metastasis: Wnt signaling-driven interventions for
metastasis restriction.” Cancers 8.6 (2016): 59.

29) Burock, Susen, et al. “Phase II trial to investigate
the safety and efficacy of orally applied niclosamide in
patients with metachronous or sychronous metastases
of a colorectal cancer progressing after therapy: the
NIKOLO trial.” BMC Cancer 18 (2018).

p 316 Mebendazole

Case Report: Metastatic Colon Cancer Remission

In 2014, Drs. Peter Nygren and Rolf Larsson
reported a case of a 74-year-old male with metastatic
colon cancer refractory to chemotherapy.
The patient was started on mebendazole
100 mg oral capsule twice a day, after which
CAT Scans showed near complete remission of
metastatic lung lesions, and partial remission
of liver lesions and nodes, with no reported
adverse effects. However, the drug did cause
liver enzyme elevation. (11)

11) Nygren, Peter, and Rolf Larsson. “Drug repositioning
from bench to bedside: Tumour remission by the
antihelmintic drug mebendazole in refractory metastatic
colon cancer.” Acta Oncologica 53.3 (2014):


p 330

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.

Mifepristone Induces Apoptosis in Cancer Cells

As mentioned above, mifepristone has a second
anti-cancer mechanism directly inducing
apoptosis in cancer cells at appropriate concentrations.
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)

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.

Mifepristone for Colon Cancer

In 2009, Dr. Check’s group found improvement
of quality of life and prolonged survival
with mifepristone 200 mg per day in two
patients with stage 4 colon cancer with extensive
metastatic disease. The metastatic disease
did not regress; instead, it appeared to stabilize,
the quality of life improved, and the drug
was well tolerated. (21)

21) Check, Jerome H., et al. “Mifepristone may halt
progression of extensively metastatic human adenocarcinoma
of the colon-case report.” Anticancer
research 29.5 (2009): 1611-1613.

p 344

Likewise in 2019, Mr. Chiara Marchiori et
al. studied colon cancer preneoplastic lesions
finding that CD80 surface protein plays a
“major role in orchestrating immune surveillance
“ Indeed, soluble CD80 was patented in
2019 as a therapy to reverse immune suppression
in cancer patients. (21–22)


21) Marchiori, Chiara, et al. “Epithelial CD80 promotes
immune surveillance of colonic preneoplastic
lesions and its expression is increased by oxidative
stress through STAT3 in colon cancer cells.” Journal of
Experimental & Clinical Cancer Research 38.1 (2019):


p 353 Cimetiodine

In 2014, Dr. Pan Pantziarka et al. reviewed
the anti-cancer effects of cimetidine, and identification
four mechanisms.
1) Antiproliferative: Oral cimetidine blocks
histamine stimulated growth of colon cancer
cells in a mouse model.


p 361, 367 AHCC

41) Kawaguchi, Yusai. “Improved survival of patients
with gastric cancer or colon cancer when treated with
active hexose correlated compound (AHCC): effect
of AHCC on digestive system cancer.” Nat Med J 1.1
(2009): 1-6.

42) Hazama, Shoichi, et al. “Efficacy of orally administered
superfine dispersed lentinan (β-1, 3-glucan)
for the treatment of advanced colorectal cancer.”
Anticancer Research 29.7 (2009): 2611-2617.

p 375

36) Rösner, Harald, et al. “Antiproliferative/cytotoxic
effects of molecular iodine, povidone-iodine and
Lugol’s solution in different human carcinoma cell
lines.” Oncology letters 12.3 (2016): 2159-2162.

p 382

40) Thomasz, Lisa, et al. “6 Iodo-δ-lactone: A derivative
of arachidonic acid with antitumor effects in HT-29
colon cancer cells.” Prostaglandins, Leukotrienes and
Essential Fatty Acids 88.4 (2013): 273-280.

p 383

63) 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.

p 387

131) Maghsood, Faezeh, et al. “Anti-proliferative and
Anti-metastatic Potential of High Molecular Weight
Secretory Molecules from Probiotic Lactobacillus
Reuteri Cell-Free Supernatant Against Human Colon
Cancer Stem-Like Cells (HT29-ShE).” International
Journal of Peptide Research and Therapeutics (2020):

p 387

145) Ishiguro, Susumu, et al. “Cell Wall Membrane
Fraction of Chlorella sorokiniana Enhances Host
Antitumor Immunity and Inhibits Colon Carcinoma
Growth in Mice.” Integrative Cancer Therapies 19
(2020): 1534735419900555.

p 393

Mefloquin Eliminates Colon Cancer Stem Cells

In 2019, Dr. Mitsunobu Takeda et al. studied
a colon cancer mouse xenograft model,
finding that disruption of lysosomal activity
with mefloquine is the key to eliminating
CSCs. Specifically, inhibition of the endolysosomal
RAB5/7 proteins with mefloquine eliminated
colorectal CSCs. Of the three antimalarial
autophagy inhibitors, mefloquine was more
effective at lower serum concentration than
chloroquine and hydroxychloroquine

Dr. Takeda’s group write:
We expect that mefloquine may induce
depletion of CSCs and, due to a synergistic
effect, demolish the cancer hierarchy,
including cancer precursor cells, when
given in combination with cytotoxic
anti-cancer drugs … Accordingly, we
suggest that mefloquine is a promising
candidate for colon CSC-targeting therapy.

45) Takeda, Mitsunobu, et al. “Disruption of endolysosomal
rab5/7 efficiently eliminates colorectal cancer
stem cells.” Cancer research 79.7 (2019): 1426-1437


p 404

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)


p 418

Thymoquinone was also found to induce
autophagic cell death in squamous cell carcinoma
and colon cancer cell models. (18–19)

19) Chen, Ming-Cheng, et al. “Thymoquinone induces
caspase-independent, autophagic cell death in CPT-
11-resistant lovo colon cancer via mitochondrial
dysfunction and activation of JNK and p38.” Journal
of agricultural and food chemistry 63.5 (2015):

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
of the NF-kB pathway with induction
of apoptosis.

89) Zhang, Lida, Yangqiu Bai, and Yuxiu Yang.
“Thymoquinone chemosensitizes colon cancer cells
through inhibition of NFκB.» Oncology letters 12.4
(2016): 2840-2845.

p 436

Combined Use of Thymoquinone
with Artemisinin

The use of combined artemisinin and thymoquinone
in a hybrid compound was explored in
2018 by Drs. Gruber and Froehlich in a colon
cancer model, finding 20-fold increased activity
compared to parent compounds and even
greater potency than the chemotherapy drug
5FU. (29–30)

30) Froehlich, Tony, et al. “Synthesis of novel hybrids
of thymoquinone and artemisinin with high activity
and selectivity against colon cancer.” ChemMedChem
12.3 (2017): 226-234.

p 437

TQ Effective Independent of P53 Status
Thymoquinone triggers P53-mediated mitochondrial
apoptosis in breast and colon cancer
cell lines that do have a functioning P53 gene.
However, about half of cancers have a mutated
P53 gene. Surprisingly, thymoquinone induces
apoptosis in cancer cell lines lacking a functioning
p53. This is remarkable!

TQ Upregulates the Functioning P53 Gene
In 2010, Dr. André Wirries et al. studied TQ
derivatives in a p53-competent colorectal and
hepatoma cell line, finding induction of apoptosis
via a P53 dependent mechanism, writing:
We developed further TQ derivatives …
investigated for … activity in HCT116 colon
cancer cells and the human hepatoma
cell line HepG2. Dependent on p53 status,
these new molecules induced a cytostatic
effect at low concentrations by the upregulation
of p21…. (32)

32) Wirries, André, et al. “Thymoquinone hydrazone
derivatives cause cell cycle arrest in p53-competent
colorectal cancer cells.” Experimental and therapeutic
medicine 1.2 (2010): 369-375.

45) Norsharina, Ismail, et al. “Thymoquinone rich fraction
from Nigella sativa and thymoquinone are cytotoxic
towards colon and leukemic carcinoma cell lines.”
Journal of Medicinal Plants Research 5.15 (2011):

p 450 Clarithromyin

36) Qiao, Xinran, et al. “Azithromycin enhances anticancer
activity of TRAIL by inhibiting autophagy and
up-regulating the protein levels of DR4/5 in colon cancer
cells in vitro and in vivo.” Cancer Communications
38.1 (2018): 43.

p 470 Celecoxib

21) Maier, Thorsten Jürgen, et al. “Targeting the
beta-catenin/APC pathway: a novel mechanism to
explain the cyclooxygenase-2-independent anticarcinogenic
effects of celecoxib in human colon
carcinoma cells.” The FASEB journal 19.10 (2005):

p 481 Fasting

9) Bianchi, Giovanna, et al. “Fasting induces anti-Warburg
effect that increases respiration but reduces
ATP-synthesis to promote apoptosis in colon cancer
models.” Oncotarget 6.14 (2015): 11806.


Colon Cancer Stem Cells

In 2017, Dr. Sugong Chen et al. studied
colon CSCs in vitro using both “transcriptomic
and proteomic approaches” to identify signaling
pathways that control the colon cancer
stem cell (CCSC) population. Dr. Chen’s group
found that several components of the PI3K/
Akt/mTOR pathway were overexpressed in
CSCs, and that treatment with PI3K inhibitor
(LY294002) decreases stem cells. They write:
LY294002-treated CCSCs showed decreases
in proliferation, sphere formation and
self-renewal, in phosphorylation-dependent
activation of Akt, and in expression
of cyclin D1…. Inhibition of PI3K in vivo
reduced tumorigenicity, increased detection
of cleaved caspase 3, an indicator
of apoptosis, and elevated expression
of the inflammatory chemokine, CXCL8.
Collectively, these results indicate that
PI3K/Akt/mTOR signaling controls CCSC
proliferation and CCSC survival. (41

Note: LY294002 is the first research drug developed
as a PI3K inhibitor, developed from and
sharing structural similarity with quercetin, a
commonly available plant bioflavonoid. (42–43)
Important: the PI3K/Akt/mTOR pathway is a
CSC pathway. All OXPHOS inhibitors also inhibit
mTOR, thus serving as CSC agents.

41) Chen, Sugong, et al. “Inhibition of PI3K/Akt/mTOR
signaling in PI3KR2-overexpressing colon cancer
stem cells reduces tumor growth due to apoptosis.”
Oncotarget 8.31 (2017): 50476.



12) Vandoros, Gerasimos P., et al. “PPAR-gamma is
expressed and NF-kB pathway is activated and correlates
positively with COX-2 expression in stromal
myofibroblasts surrounding colon adenocarcinomas.”
Journal of cancer research and clinical oncology 132.2
(2006): 76-84.

13) Cherukuri, Durga, et al. “Selenomethionine regulates
cyclooxygenase-2 (COX-2) expression through
nuclear factor-kappa B (NF-kB) in colon cancer cells.”
Cancer biology & therapy 4.2 (2005): 183-188.

20) Grosch, Sabine, et al. “COX-2 independent induction
of cell cycle arrest and apoptosis in colon cancer
cells by the selective COX-2 inhibitor celecoxib.” The
FASEB journal 15.14 (2001): 2742-2744.

32) Khan, K. N. M., et al. “Enhanced cyclooxygenase-2
expression in sporadic and familial adenomatous polyposis
of the human colon.” Scandinavian journal of
gastroenterology 36.8 (2001): 865-869.

94) Han, Yi, et al. “Synergy between auranofin and
celecoxib against colon cancer in vitro and in vivo
through a novel redox-mediated mechanism.” Cancers
11.7 (2019): 931.

120) Ohira, Gaku, et al. “Preoperative chemoradiotherapy
using S-1 combined with celecoxib for advanced
lower rectal cancer: Phase I/II study.” Journal of the
anus, rectum and colon 3.1 (2019): 43-48.


150) GroSch, Sabine, et al. “COX-2 independent induction
of cell cycle arrest and apoptosis in colon cancer
cells by the selective COX-2 inhibitor celecoxib.” The
FASEB journal 15.14 (2001): 2742-2744

p 508

Diclofenac Plus Curcumin
Synergy for Colon Cancer
In 2015, Dr. Rana found the combination of
diclofenac and curcumin synergistic in a colon
cancer model, with downregulation of the PI3/
Akt pathway and activation of mitochondrial
apoptosis. (15)

15) Rana, Chandan, et al. “Downregulation of PI3-K/
Akt/PTEN pathway and activation of mitochondrial
intrinsic apoptosis by Diclofenac and Curcumin in
colon cancer.” Molecular and cellular biochemistry
402.1-2 (2015): 225-241.

p 510

Sulindac and EGFR inhibitor for FAP
The NSAID, Sulindac, is a nonspecific COX
inhibitor. Its metabolite, sulindac sulfide is a
5-LOX inhibitor. (70)

Sulindac clinical trials shows significant
reduction in colonic polyps in familial adenomatous
polyposis FAP. The usual treatment for
FAP is surgical removal of the colon. However,
these patients remain at risk for duodenal
polyps, considered premalignant for duodenal
cancer. Sulindac, combined with the EGFR
inhibitor erlotinib, has been found successful
in reducing both colonic polyps and duodenal
polyp formation in FAP. (50–55)

50) Labayle, Denis, et al. “Sulindac causes regression
of rectal polyps in familial adenomatous polyposis.”
Gastroenterology 101.3 (1991): 635-639.

51) Cruz–Correa, Marcia, et al. “Long-term treatment
with sulindac in familial adenomatous polyposis: a prospective
cohort study.” Gastroenterology 122.3 (2002):

52) Lawrence, Leah. “Polyp Burden Drops With
Sulindac/Erlotinib Combo in FAP.” ONCOLOGY 34.5

53) Ulusan, Ahmetmursel, et al. “Optimizing erlotinib
plus sulindac dosing regimens in a preclinical model
of FAP.” (2019): 5074-5074.

54) Delker, Don A., et al. “Chemoprevention with
cyclooxygenase and epidermal growth factor receptor
inhibitors in familial adenomatous polyposis patients:
mRNA signatures of duodenal neoplasia.” Cancer
Prevention Research 11.1 (2018): 4-15.

56) Aono, Yuichi, et al. “Sulindac sulfone inhibits the
mTORC1 pathway in colon cancer cells by directly targeting
voltage-dependent anion channel 1 and 2.”
Biochemical and biophysical research communications
505.4 (2018): 1203-1210.

58) Gong, Eun-Yeung, et al. “Combined treatment
with vitamin C and sulindac synergistically induces
p53-and ROS-dependent apoptosis in human colon
cancer cells.” Toxicology letters 258 (2016): 126-133.

59) Williamson, Tara, et al. “Mebendazole and a
non-steroidal anti-inflammatory combine to reduce
tumor initiation in a colon cancer preclinical model.”
Oncotarget 7.42 (2016): 68571.


60) Pouyafar, Ayda, et al. “Treatment of cancer stem
cells from human colon adenocarcinoma cell line
HT-29 with resveratrol and sulindac induced mesenchymal-
endothelial transition rate.” Cell and tissue
research 376.3 (2019): 377-388.

p 521 Aspirin

In 2017, Dr. L. M. Lichtenberger et al. studied
the effects of aspirin in a mouse model of
colon cancer in vitro and in vivo, finding that
aspirin’s ability to irreversibly inhibit COX-1
mediated platelet activation confers its remarkable
anti-cancer efficacy. (77)

p 532 Statins

132) Palko-Łabuz, Anna, et al. “MDR reversal and
pro-apoptotic effects of statins and statins combined
with flavonoids in colon cancer cells.” Biomedicine &
Pharmacotherapy 109 (2019): 1511-1522.

p 528 Dipyridamole

55) Grem, Jean L., and Paul H. Fischer. “Augmentation
of 5-fluorouracil cytotoxicity in human colon cancer
cells by dipyridamole.” Cancer research 45.7 (1985):

p 532

132) Palko-Łabuz, Anna, et al. “MDR reversal and
pro-apoptotic effects of statins and statins combined
with flavonoids in colon cancer cells.” Biomedicine &
Pharmacotherapy 109 (2019): 1511-1522.


p 534 Tocotrienol

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)


14) Husain, Kazim, et al. “Vitamin E delta-tocotrienol
targets human colon cancer stem cells and inhibits
colon cancer metastasis and induces apoptosis.”
(2016): 3839-3839.

15) Wada, S., et al. “δ-Tocotrienol suppresses tumorigenesis
by inducing apoptosis and blocking the COX-2/
PGE2 pathway that stimulates tumor–stromal interactions
in colon cancer.” Journal of Functional Foods 35
(2017): 428-435.


22) Balagoni, Harika, et al. “Cytotoxic Effects of
Metformin and Gamma-Tocotrienol on Colon Cancer
Cells: 153.” American Journal of Gastroenterology 112
(2017): S77.

38) Yang, Chao. Mechanistic Investigation of
Resveratrol-, Pterostilbene-, and δ-Tocotrienol-Mediated
Anti-Nf-κb Activity and the Effect of δ-Tocotrienol
on Colitis-Promoted Colon Tumorigenesis in Mice.
Diss. Purdue University, 2017.




Pantziarka, Pan, et al. “Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent.” ecancermedicalscience 8 (2014).

Screening of compounds for activity against colon cancer cell lines also identified MBZ as a candidate molecule in work by Nygren and colleagues [20]. The authors set out to screen 1600 existing drugs for activity against two well-established colon cancer cell lines (HCT 116 and RKO) and found 64 candidate drugs, including a cluster of benzimidazoles (albendazole, mebendazole, oxybendazole and fenbendazole). Of these, further analysis was performed on MBZ and albendazole because, in the words of the authors, ‘they are registered pharmaceuticals for clinical use in humans, thus easily accessible for clinical testing’.
20) Nygren, Peter, et al. “Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer.” Journal of cancer research and clinical oncology 139.12 (2013): 2133-2140.

Five colon cancer cell lines, including those used in the primary screen, and three cell lines with non-malignant phenotypes were subsequently tested for response to MBZ (Fig. 4c). All 5 colon cancer cell lines showed a MBZ IC50 of <5 µM whereas the drug was largely inactive in the non-malignant cell line models, thus indicating a potentially good therapeutic index in colon cancer (Fig. 4c). Indeed as a first indication of this possibility, a patient with refractory metastatic colon cancer was treated with MBZ at the standard anthelmintic dose of 100 mg twice daily. The patient experienced no subjective adverse effects at all from the drug and computerized tomography evaluation after six weeks of therapy showed near complete remission of the metastases in the lungs and lymph nodes and a good partial remission in the liver (case report accepted for publication in Acta Oncologica).

Niclosamide Combination with Metformin
Kang, Hee Eun, et al. “Metformin and niclosamide synergistically suppress Wnt and YAP in APC-mutated colorectal cancer.” Cancers 13.14 (2021): 3437.

Hyperactivation of the canonical Wnt and inactivation of the Hippo pathway are well-known genetic backgrounds for familial adenomatosis polyposis (FAP) and colorectal cancer (CRC), although the reciprocal regulation between those pathways is not yet clear. In this study, we found that Axin2, a bona fide downstream target of canonical Wnt, activates the Hippo pathway in APC-mutated CRC, limiting the therapeutic potential of niclosamide on advanced CRC through the inactivation of the Hippo pathway. To overcome the limitation, we combined niclosamide with AMPK activator metformin to activate Hippo and found that this combination synergistically suppressed canonical Wnt and activated Hippo in APC-mutated CRC. Using patient-derived cancer organoid and an APC-MIN mice model, we found the combinatory approach to be effective for APC-mutated CRC. Our results provide not only the reciprocal link between Wnt and Hippo in APC-mutated CRC, but they also provide an effective therapeutic approach with clinically available drugs for FAP and CRC patients.

May not be in the Book


DCA and Omeprazole

Ishiguro, Tatsuaki, et al. “Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors.” Oncology letters 3.3 (2012): 726-728.
Ishiguro, Tatsuaki, et al. “Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report.” Hepato-gastroenterology 59.116 (2012): 994-996.
Ishiguro, T., et al. “Co-treatment of dichloroacetate and omeprazole dramatically reduced the pain of pancreatic and bile duct cancer; possible blockade of their invasion.” Abdominal Oncology 1 (2013): 1-4.

DCA plus Metformin

Korsakova, Laura, Jan Aleksander Krasko, and Edgaras Stankevicius. “Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth In Vitro and In Vivo.” in vivo 35.1 (2021): 341-348.
Colon Cancer/ DCA
Khan, Akbar, Doug Andrews, and Anneke C. Blackburn. “Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy (Case report).”

Last updated 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