Cracking Cancer Toolkit:

Using Repurposed Drugs for Cancer Treatment

Jeffrey Dach MD
7450 Griffin Road
Suite 190
Davie, FL 33021
954-792-4663

© Copyright 2021 Jeffrey Dach MD

Slides Available At: http://jeffreydachmd.com

 The Chemotherapy Paradigm
• Old Paradigm: Chemotherapy
• New Paradigm: Cancer as a Metabolic Disease.
• Chemotherapy Can Not Eradicate Cancer Stem
Cells. We Need New Therapies that can.

• Chemo Causes Massive Inflammation, via

Activation of NF-kB, and COX-2.
• Worsens Cancer Induced Immunosuppression
Pecqueur, Claire, et al. “Targeting metabolism to induce cell death in cancer cells and cancer
stem cells.” International journal of cell biology 2013 (2013).

© Copyright 2021 Jeffrey Dach MD

Cancer Stem Cells
 Cancer Stem Cell Meetings
• Oncologists attend national CSC
meetings, yet remain oblivious
upon returning to the hospital,
continuing old chemotherapy
protocols as if nothing has
changed.
© Copyright 2021 Jeffrey Dach MD
 Cancer Stem Cells - Quote
• “CSCs are responsible for clinical failure
of currently available oncological
therapies because they survive
treatment with hormones, radiation,
chemotherapy, and molecularly
targeted drugs. How to eliminate CSCs
has become a research focus in recent
years.” (Jiang,2020)
Jiang, Lin-Li, and Lei Liu. "Effect of metformin on stem cells: Molecular mechanism and
clinical prospect." World Journal of Stem Cells 12.12 (2020): 1455.
“The Successful Elimination of Cancer
requires anti-cancer therapy affecting both differentiated cancer
cells and CSCs…. At present, conventional therapy that includes
radio-, chemo-, and immunotherapy kills rapidly proliferating and
differentiated cells. These treatments may cause the tumor to
shrink but will not prevent tumor recurrence. Thus, a
combination of treatments targeting both rapidly
proliferating cancer cells and quiescent or slow-proliferating CSCs
would be ideal…A reversal of tumor metabolism to
“normal” might impair tumor growth of cancer cells, causing
tumor regression, and differentiation/sensitization
to cell death of CSCs, impairing the recurrence of the tumor.”
(Pecquer, 2013)

Pecqueur, Claire, et al. “Targeting metabolism to induce cell death in cancer cells and cancer
stem cells.” International journal of cell biology (2013).
 Can Chemotherapy
Kill Cancer Stem Cells ?
• “Generally, conventional chemotherapy
can only inhibit tumor growth and lead
to drug resistance, but cannot kill
Cancer Stem Cells”. (Du, Fang-Yu, 2019)
Du, Fang-Yu, et al. “Targeting cancer stem cells in drug discovery: Current state and future
perspectives.” World journal of stem cells 11.7 (2019): 398.
 New Technologies
Driving the New Paradigm

• Automated High Thru-Put Drug Screening

• PET Scan Imaging with 18 FDG isotope
• Internet Message Groups. (Social Media)
Flobak, Åsmund, et al. "A high-throughput drug combination screen of targeted small
molecule inhibitors in cancer cell lines." Scientific data 6.1 (2019): 1-10.
Gupta, Piyush B., et al. "Identification of selective inhibitors of cancer stem cells by high-
throughput screening." Cell 138.4 (2009): 645-659.
Harvey, Alan L., and Ian A. Cree. "High-throughput screening of natural products for cancer
therapy." Planta medica 76.11 (2010): 1080-1086.

© Copyright 2021 Jeffrey Dach MD

 Cancer as Metabolic Disease
• Warburg Effect (Shift from OXPHOS to Glycolysis)
High Lactate Generation.
• High Glucose Uptake Seen on PET Scan.
• Hexokinase II Relocated to the VDAC on Outer
Mitochondrial Membrane.
• Resulting in Immortalization of Cancer Cell-
Preventing Apoptosis.
• Resulting in Massive Glucose Uptake and
Utilization
• Metabolic Plasticity- Switching Pathways
© Copyright 2021 Jeffrey Dach MD
Three Pillars of Cancer Cell Metabolism

GLYCOLYSIS OXPHOS Autophagy

© Copyright 2021 Jeffrey Dach MD
 Metabolic Plasticity of the
Cancer Cell
GLYCOLYSIS OXPHOS Autophagy
The metabolic plasticity of the cancer cell
requires combination of two or more anti-
cancer agents to block all three pathways,
thereby achieving “Synthetic Lethality.”

© Copyright 2021 Jeffrey Dach MD

Fourth Pillar

Restore
Host
Immune
Surveillance
© Copyright 2021 Jeffrey Dach MD
Fifth Pillar

Upregulation
Inflammatory
Pathways
NF-kB, IL-6
cytokines
© Copyright 2021 Jeffrey Dach MD
 The Cancer Stem Cell
• Exists in Dormant State
• Negative on PET Scan
• Cancer Relapse after
Chemotherapy
• Exists in Energetic State –
CTC Circulating Tumor Cells
 Cancer Stem Cell Pathways

•Wnt/Beta Catenin
•Hedgehog
•Notch
Targeting these pathways
eliminates cancer stem cells
© Copyright 2021 Jeffrey Dach MD
 Cancer Stem Cell Pathway
Wnt Signaling
• “Our results suggest that the inability of
conventional chemotherapy to kill MCL-
ICS (Lymphoma Cancer Stem Cells) can
be overcome by adding inhibitors of
Wnt signaling” (Mathur, Rohit, et al, 2015)
Mathur, Rohit, et al. “Targeting Wnt pathway in mantle cell lymphoma-initiating cells.”
Journal of hematology & oncology 8.1 (2015): 63

© Copyright 2021 Jeffrey Dach MD

Wnt Cancer Stem Cell Pathway
Wnt On Han, Jae-Ik, and Ki-
Jeong Na. "Wnt/β-
Catenin signaling
pathway in canine
skin melanoma
and a possibility as
a cancer model for
human skin
melanoma."
Melanoma in the
Clinic-Diagnosis,
Management and
Complications of
Malignancy.
IntechOpen, 2011.
Cyclin D1
S100A4 gene C-Myc
 Wnt Cancer Stem Cell Pathway
Wnt On Wnt ON: βeta-catenin is
NOT degraded, and
instead the accumulated
β-catenin enters the
nucleus and activates the
target gene TCF/LEF, and
c-Myc and Cyclin D1.

Han, Jae-Ik, and Ki-Jeong Na. "Wnt/β-Catenin signaling pathway in melanoma."

Melanoma in the Clinic-Diagnosis, Management of Malignancy. IntechOpen, 2011.
Wnt Cancer Stem Cell Pathway
Wnt OFF Han, Jae-Ik, and Ki-
Jeong Na. "Wnt/β-
Catenin signaling
pathway in canine
skin melanoma
and a possibility as
a cancer model for
human skin
melanoma."
Melanoma in the
Clinic-Diagnosis,
Management and
Complications of
Malignancy.
IntechOpen, 2011.
 Wnt OFF
Niclo degrades LP6
Melatonin

Pyrvinium
Ivermectin
 Wnt Cancer Stem Cell Pathway
Wnt OFF: In the absence of
Wnt OFF Wnt signals, a cellular
complex degrades β-catenin,
so there is no entry of the
β-catenin protein into the
nucleus, the gene TCF/LEF is
suppressed, and no nuclear
transcription of Cyclin D1 or
other growth signals takes
place.
Han, Jae-Ik, and Ki-Jeong Na. "Wnt/β-Catenin signaling pathway in melanoma."
Melanoma in the Clinic-Diagnosis, Management of Malignancy. IntechOpen, 2011.
 Repurposed Drugs Targeting Wnt Signaling
• Metformin (Anti-Diabetic Drug, OXPHOS inhibitor)
• Ivermectin (Specific WNT-TCF Blocker at low
micromolar concentrations.)
• Niclosamide (Hookworm, OXPHOS Uncoupler)
• Pyrvinium (hookworm,pinworm)
• Mefloquine/Chloroquine (Antimalarial,
Autophagy Inhibitors)
• Doxycycline/ Clarithromycin/Azithromycin
• Sulfasalazine (Rheumatology, Xct inhibitor )
• VIT A, Fenretinde, ATRA, (Pro Myleo Leukemia)
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.
 Metformin Oxphos Inhibitor
• First Line Diabetic Drug (French Lilac plant)
• Targets Cancer Stem Cells.
• Docks in the HK II binding site, blocks function,
separates HK II from VDAC on the outer
mitochondrial membrane.
• Accumulates in Mito, Inhibits Complex I ETC.
• Activates AMPk, Inhibits mTOR, induces
“Protective Autophagy”, Synergy wth chloroquine
Salani, Barbara, et al. “Metformin impairs glucose consumption and survival in Calu-1 cells by
direct inhibition of hexokinase-II.” Scientific reports 3 (2013).
Rattan, Ramandeep et al. "Metformin: an emerging new therapeutic option for targeting
cancer stem cells." Journal of oncology 2012 (2012).
© Copyright 2021 Jeffrey Dach MD
 Ivermectin Top Candidate, Blocks TCF Gene
Alice Melotti et al. used a transcriptional reporter assay for
TCF activity driven by ß-catenin to test a collection of
1,040 drugs. Only one agent, ivermectin, perfectly
tracked the profile induced by blocking the TCF gene,
blocks the Wnt pathway, and kills cancer stem cells…!!!!
(2014)
Sharmeen et al. at the University of Toronto screened a
library of 100 drugs for activity against a leukemic cell line.
They reported ivermectin as the top candidate for
inducing leukemic cell death at low micromolar
concentrations. (2010)
Melotti, Alice, et al. “The river blindness drug Ivermectin inhibit WNT‐TCF pathway responses
in human cancer.” EMBO molecular medicine (2014): e201404084.
Sharmeen, et al. “Antiparasitic ivermectin induces hyperpolarization and cell death in
leukemia cells.” Blood 116.18 (2010): 3593-3603 © Copyright 2021 Jeffrey Dach MD
 Niclosamide
• Antiparasitic for Hookworm
• Inhibits OXPHOS-Mitochondrial Uncoupler.
• Targets CSC, Wnt and Notch inhibitor
• Downregulates NF-Kb
• Effective for Ovarian CA w/wo chemo
• Effective for P53 deficient/mutated cell types
• Reverses EMT Epithelial to Mesenchymal Trans
• Blocks Late Stage Autophagy
• Inhibits antegrade lysosomal trafficking
Pan, Jing-Xuan, Ke Ding, and Cheng-Yan Wang. “Niclosamide, an old antihelminthic agent,
demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem
cells.” Chinese journal of cancer 31.4 (2012): 178.
 Niclosamide for MM
• “At clinically achievable nontoxic concentrations,
[Niclosamide] killed Multiple Myeloma cell lines
as efficiently or better than chemotherapy and
anti-myeloma drugs with little impact on normal
cells. More importantly there was rapid reduction
in light chain production [the clonal antibodies
which cause amyloid deposits and renal
impairment].” (Khanim, 2011)

Khanim, F. L., et al. “Redeployment-based drug screening identifies the anti-helminthic

niclosamide as anti-myeloma therapy that also reduces free light chain production.” Blood
cancer journal 1.10 (2011): e39.
© Copyright 2021 Jeffrey Dach MD
 Pyrvinium Oxphos Inhibitor
• Pyrvinium degrades cytosolic Beta-Catenin,
resulting in potent inhibition of Wnt signaling at
low concentrations (10 nanoMolar). (Thorne 2010)
• OXPHOS Inhibitor Accumulates in mitochondria
with inhibition of complex I and II in the electron
transport chain.
• Inhibits Glutathione Uptake from TME
• Potent Androgen Receptor Blocker (BPH)

Thorne, Curtis A., et al. “Small-molecule inhibition of Wnt signaling through activation of
casein kinase 1α.” Nature chemical biology 6.11 (2010): 829.

© Copyright 2021 Jeffrey Dach MD

 All OxPhos Inhibitors
Are Cancer Stem Cell Agents
• All OXPHOS inhibitors are Wnt pathway
inhibitors and therefore may serve as
valid anti-CSC agents. This is due to the
“Mitochondrial-Wnt Signaling Axis”
(Roberto Costa 2019)
Costa, Roberto, et al. “Impaired mitochondrial ATP production downregulates Wnt signaling
via ER stress induction.” Cell reports 28.8 (2019): 1949-1960.
© Copyright 2021 Jeffrey Dach MD
Botanicals Targeting Cancer Stem Cells
Wnt Pathway Inhibitors
• Sulforaphane • Resveratrol/
• Curcumin Pterostilbene
• Berberine • Silibin (Milk Thistle)
• Parthenolide (feverfew) • (Garlic) Diallyl
• EGCG (green tea) trisulfide Allicin
• Quercetin • Vitamin D3
• Baicalin (Chinese • Most are OXPHOS
Skullcap) inhibitors
Scarpa, E. S., and P. Ninfali. “Phytochemicals as Innovative Therapeutic Tools against Cancer
Stem Cells.” International journal of molecular sciences 16.7 (2014): 15727-15742.
 Repurposed Drugs Considerations
• Are we able to reach therapeutic blood levels
using standard dosages?
• The Drug is Effective in animal models, but is the
Drug Effective in Humans?
• Is the drug active against CSCs?
• Drug Toxicity: What are adverse effects? Is the
drug too toxic for human use?
• Drug Interactions: CYP450 enzyme system?

© Copyright 2021 Jeffrey Dach MD

 More References
(1) Liskova, Alena, et al. “Dietary Phytochemicals Targeting Cancer Stem Cells.” Molecules
24.5 (2019):899.
(2) Das, Plabon K., et al. “Natural Compounds Targeting Cancer Stem Cells: A Promising
Resource for Chemotherapy.” Anti-Cancer Agents in Medicinal Chemistry (2019).
(3) Chan, Marion et al “Targeting cancer stem cells with dietary phytochemical-Repositioned
drug combinations.” Cancer Letters 433 (2018): 53-64.
(4) McCubrey, James A., et al. "Effects of resveratrol, curcumin, berberine and other
nutraceuticals on cancer development, cancer stem cells." Aging 9.6 (2017): 1477.
(5) Ortiz, Luis Miguel Guamán, et al. “Berberine, an epiphany against cancer.” Molecules 19.8
(2014):12349-12367.
(6) Mokhtari, Reza Bayat, et al. “The role of Sulforaphane in cancer chemoprevention and
health benefits: a mini-review.” J of Cell Comm and Signaling 12.1 (2018): 91-101.
(7) Papandreou, Ioanna, et al. “Plant stilbenes induce endoplasmic reticulum stress and anti-
cancer activity enhanced by inhibitors of autophagy.” Exp Cell Res 339.1 (2015): 147-153.
(8) Steele, A. J., et al. “Parthenolide (feverfew) induces selective apoptosis of B-chronic
lymphocytic leukemia cells in vitro.” Leukemia 20.6 (2006): 1073-1079.
(9) Eo, Hyun Ji, Gwang Hun Park, and Jin Boo Jeong.“Inhibition of Wnt signaling by silymarin
in human colorectal cancer cells.” Biomolecules & Therapeutics
(10)Haghi, Atousa, et al. “A comprehensive review on curcumin, quercetin, and allicin, in the
treatment of gastric cancer.” Journal of Gastrointestinal Cancer 48.4 (2017): 314-320.
 Hallmarks of Cancer Cells
Hanahan and Weinberg
• Reprogrammed Energy Metabolism – The
Warburg Effect (HKII-VDAC)
• Evasion of Apoptosis (BCL2)
• Evasion of the Immune System (PIBF)
• Upregulated Inflammation (NF-kB)
• Upregulated Growth Signals (VEGF, PDGF,EGF,E2)

1) Hanahan, Douglas, and Robert A. Weinberg. “The hallmarks of cancer.” cell 100.1 (2000):
57-70.
2) Hanahan, Douglas, and Robert A. Weinberg. “Hallmarks of cancer: the next generation.”
cell 144.5 (2011): 646-674.
All Hallmarks Are Downstream of
Metabolic Disturbance
• “All recognized hallmarks of cancer are considered
downstream epiphenomena of the initial
disturbance of cellular energy metabolism. The
disturbances in tumor cell energy metabolism can
be linked to abnormalities in the structure and
function of the mitochondria.” (Thomas Seyfried
2013).

1) Seyfried, Thomas N., et al. “Cancer as a metabolic disease: implications for novel
therapeutics.” Carcinogenesis 35.3 (2013): 515-527.
© Copyright 2021 Jeffrey Dach MD
 Reprogramming Energy Metabolism
• The Warburg Effect/Fermentation.
• Carbon Shunted Away from OXPHOS
towards GLYCOLYSIS (PDK upregulated,
Inhibiting PDC)
• High Lactate Generation/Accumulation.
• HKII - Translocated to the VDAC
• Provides ATP for Glycolysis Pathway
• Prevents Mitochondrial Apoptosis.
Phan, Liem Minh, "Cancer metabolic reprogramming: importance, main features, and
potentials for precise targeted anti-cancer therapies." Cancer biology & med 11.1 (2014): 1.
Ward, Patrick S., and Craig B. Thompson. "Metabolic reprogramming: a cancer hallmark
even warburg did not anticipate." Cancer cell 21.3 (2012): 297-308.
Reprogramming Energy
Metabolism

Hexokinase-II
Translocated
to the VDAC
© Copyright 2021 Jeffrey Dach MD
 HKII-VDAC

VDAC • Hexokinase II
attached to VDAC
on mitochondrial
membrane,
utilizing ATP to
convert glucose
to G6-P
• Mathupala, Ko, and P. L.
Pedersen. “Hexokinase
II: cancer’s double-
edged sword when
bound to mitochondria.”
Oncogene 25.34 (2006):
4777.
 HKII-VDAC
• Release of
HKII from
Bcl2 VDAC
Bcl2 HKII induces
Apoptosis
HKII • BCL2 goes
with it.
• Fig 3 Mathupala, Ko,
and P. L. Pedersen.
“Hexokinase II:
VDAC cancer’s double-edged
sword when bound to
VDAC mitochondria.”
Oncogene 25.34
 Repurposed Drugs
Detach HKII from VDAC
Itraconazole
Fenofibrate
Aspirin
Metformin

Head, Sarah A., et al. “Antifungal drug itraconazole targets VDAC1 to modulate the
AMPK/mTOR signaling axis in endothelial cells.” Proceedings of the National
Jan, Chia-Ing, et al. “Fenofibrate suppresses oral tumorigenesis via reprogramming
metabolic processes: drug repurposing for cancer.” Int J Bio Sci 12.7 (2016): 786.
Academy of Sciences 112.52 (2015): E7276-E7285.
Tewari, Debanjan, et al. “Aspirin induces cell death by directly modulating mitochondrial
voltage-dependent anion channel (VDAC).” Scientific reports 7.1 (2017): 1-9.
© Copyright 2021 Jeffrey Dach MD
 Itraconazole (Sporonox) Antifungal
Itraconazole Binds to VDAC and Disrupts HK2
(Hexokinase 2) from mitochondria.
Inhibits Wnt and Hedgehog (Hh) Pathways.
Inhibits Akt/mTOR, induces“Protective
Autophagy”
Inhibits 5-LOX and VEGF
Tsubamoto, Hiroshi, et al. "Repurposing itraconazole as an anticancer agent."
Oncology letters 14.2 (2017): 1240-1246.
Head, Sarah A., et al. “itraconazole targets VDAC1 to modulate the
AMPK/mTOR signalin.” Proc Nat Acadof Sci 112.52 (2015): E7276-E7285.
Head, Sarah A., et al. “Simultaneous Targeting of NPC1 and VDAC1 by
Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and
Angiogenesis.” ACS chemical biology 12.1 (2016): 174-182.
© Copyright 2021 Jeffrey Dach MD
 Fenofibrate Lipid Drug
Accumulates in mitochondria, inhibits Complex
One of the ETC.
Interrupts the Warburg Effect
Disrupts HK-2 from the VDAC,
Destroys BCL-2, and restores apoptosis.
Blocks FASN (Fatty Acid Synthetase),
Activates PPAR-alpha
Potentiated by vitamin A derivatives.
Dual GLYCOLYSIS and OXPHOS inhibitor
Lian, Xin, et al. "Anticancer properties of fenofibrate: a repurposing use." Journal of
Cancer 9.9 (2018): 1527.
 Aspirin - Glycolysis Inhibitor
Targets VDAC, Detaches HK2 from the VDAC.
Glycolysis Inhibitor, Reduces Glycolytic CSC.
Aspirin/Metformin Combination Striking synergy.
Combined with EGFR-TKIs shows considerable synergy,
overcomes TKI drug resistance.
Combined with chemotherapy reduces inflammation,
NF-kB, reducing numbers of cancer stem cells.
Inhibit platelets and modifies the genetic expression of
the cancer cell.

Yue, Wen, et al. “Metformin combined with aspirin significantly inhibit pancreatic cancer
in vitro and in vivo by suppressing anti-apoptotic proteins Bcl-2.” Oncotarget 6.25 (2015
Abdelmonsif, Doaa Ali, et al. “Targeting AMPK, mTOR and β-catenin by combined
metformin and aspirin therapy in HCC.” Molecular diag & ther 22.1 (2018): 115-127.
 Natural Substances
Bind to and Detaches HKII from VDAC
• Methyl Jasmonate
• Chinese Skullcap (Baicalin, Oroxylin A)
• Curcumin
• CBD (Cannabidiol)
Goldin, N., et al. “Methyl jasmonate binds to and detaches mitochondria-bound hexokinase.”
Oncogene 27.34 (2008): 4636-4643
Wei, L., et al. “Oroxylin A induces dissociation of hexokinase II from the mitochondria and
inhibits in breast carcinoma.” Cell death & disease 4.4 (2013): e601.
Tewari, Debanjan, et al. “Modulation of the mitochondrial voltage dependent anion channel
(VDAC) by curcumin.” Biochimica et Biophysica Acta (BBA)- Biomembranes 1848.1 (2015):
151-158.
Rimmerman, N., et al. “Direct modulation of the outer mitochondrial membrane channel,
voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for
cannabinoid-induced cell death.” Cell death & disease 4.12 (2013): e949-e949.
Three Pillars of Cancer Cell Metabolism

GLYCOLYSIS
Warburg Effect
© Copyright 2021 Jeffrey Dach MD
 Metabolic Reprogramming in Cancer Cells
“Inhibition of PDC activity by pyruvate
dehydrogenase kinase [PDK]–mediated
phosphorylation has been associated with the
pathobiology of …cancer. Consequently, the
PDC/PDK axis has long been a therapeutic
target.” (Stacpoole, Peter 2017)
Inhibition of PDC Reprograms from
Mitochondrial OXPHOS to Glycolysis in
Cytoplasm.
Stacpoole, Peter W. “Therapeutic targeting of the pyruvate dehydrogenase
complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer.” JNCI: Journal
of the National Cancer Institute 109.11 (2017).
© Copyright 2021 Jeffrey Dach MD
 PDH/PDC PDH Cycle
Thiamine
PDC- The
Pyruvate
Dehydrogenase
Complex in
Cancer. Paul M.
Bingham and
Zuzana Zachar in
Biochemistry,
Genetics and
Molecular
Biology edited by
Rosa Angela
Pyruvate Canuto,
Dehydrogenase Published:
Complex November 14,
2012. (15)
 DCA Dichloroacetic Acid
DCA (Dichloroacetate) - Pyruvate Analog, Not
Metabolized.
Strongly Inhibits PDK Function, and Activates PDH
(Pyruvate Dehydrogenase), which Activates
Mitochondrial OXPHOS, and Inhibits Glycolysis in
Cytoplasm (Warburg Effect)
Thiamine and R-Alpha Lipoic Acid (Poly MVA) -
Co-factors needed to prevent DCA INDUCED
Neuropathy.
Tataranni, Tiziana, and Claudia Piccoli. "Dichloroacetate (DCA) and cancer: an overview
towards clinical applications." Oxidative medicine and cellular longevity 2019 (2019).

© Copyright 2021 Jeffrey Dach MD

 DCA Dichloroacetic Acid

Tataranni, Tiziana, and Claudia Piccoli. "Dichloroacetate (DCA) and cancer: an overview
towards clinical applications." Oxidative medicine and cellular longevity 2019 (2019).
 DCA Dichloroacetic Acid

Tataranni, Tiziana, and Claudia Piccoli. "Dichloroacetate (DCA) and cancer: an overview
towards clinical applications." Oxidative medicine and cellular longevity 2019 (2019).
 “Truly Big Advance”
DCA - Glycolysis Inhibitor
“The combined use of DCA and Poly-MVA
has been one of the Truly Big Advances in
integrative cancer therapies in the past 20
years. (Paul Anderson, 2018)”
Poly-MVA is Alpha Lipoic Acid, Thiamine
and Palladium, Liquid Polymer.
Stengler, Mark and Anderson Paul. Outside the Box Cancer Therapies: Alternative
Therapies that Treat and Prevent Cancer. Hay House, Inc, 2018.
© Copyright 2021 Jeffrey Dach MD
 DCA (GLYCOLYSIS Inhibitor) Synergy with
OXPHOS and Autophagy Inhibitors
DCA Plus Metformin (OXPHOS Inhibitor)

DCA Plus Propranolol (OXPHOS Inhibitor and

Autophagy Inhibitor)

DCA (Glycolysis Inhibitor) Plus Omaprazole (PPI)

Autophagy Inhibitor

Villalba, Martin, et al. “Chemical metabolic inhibitors for the treatment of blood-borne
cancers.” Anti-Cancer Agents in Medicinal Chemistry 4.2 (2014): 223-232.
 Propranolol Beta Blocker
“Most Striking Discovery to Date.”
Inhibits OXPHOS (ATP Reduces Tumor
synthase). Proliferation.
Activates GLYCOLYSIS Anti-Angiogenic
Reduces HK2 protein effects.
levels. Restores Anti-tumor
Inhibits Autophagy Immune Function.
(chloroquine-like) Decreases mortality,
metastases, recurrence.

Pantziarka, Pan, et al. "Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-

cancer agent." ecancermedicalscience 10 (2016).
 Propranolol - Beta Blocker
“Most Striking Discovery to Date.”

Synergy with DCA

Blocks All Three Metabolic Pathways.

Pantziarka, Pan, et al. "Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-

cancer agent." ecancermedicalscience 10 (2016).
 DCA Immune System Effects
DCA restores host anti-cancer immunity by
decreasing acidic lactate in the micro-
environment,
By Increasing IL-12 and “modulating cytokines
toward T-helper 1 (TH1) lymphocyte function.”

Badr, Mujtaba M., et al. “Dichloroacetate modulates

cytokines toward T helper 1 function via induction of the
interleukin-12–interferon-gamma pathway.”
OncoTargets and therapy 7 (2014): 193.
© Copyright 2021 Jeffrey Dach MD
Three Pillars of Cancer Cell Metabolism

OXPHOS
© Copyright 2021 Jeffrey Dach MD
OXPHOS -The Mitochondrion

VDAC
 Metformin – OXPHOS Inhibitor
Diabetic Drug from French Lilac Plant
Metfromin Users - 30–50 % Reduction in cancer.
Metformin Inhibits Complex I of ETC.
Activates AMP-kinase (AMPK)
Inhibits mTOR signaling.
OXPHOS Inhibitor- Shifts to Glycolytic Phenotype
Synergy with Glycolysis Inhibitors (DCA)
Metformin docks in the HKII binding site,
blocking its function, separates HKII from VDAC
membrane.
Yu, Hong, et al. "The potential effect of metformin on cancer: an umbrella review."
Frontiers in endocrinology 10 (2019): 617.
Metformin – OXPHOS/Wnt Inhibitor
“Perturbation of mitochondrial function
using a number of inhibitors can cause
decreased Wnt activity both in vitro and in
vivo.” (Costa, Roberto, 2019)
All Mitochondrial OXPHOS inhibitors are
also Anti-CSC agents.
Costa, Roberto, et al. “Impaired mitochondrial ATP production downregulates
Wnt signaling via ER stress induction.” Cell reports 28.8 (2019): 1949-1960.
Zhang, Xiaonan, et al. “Targeting mitochondrial function to treat quiescent
tumor cells in solid tumors.” International journal of molecular sciences 16.11
(2015): 27313-27326.
Metformin – Detaches HKII from VDAC
“HK2 inhibition by metformin causes
release of this enzyme [HK2] from the
outer membrane of mitochondria, thus
leading to the activation of apoptotic
signals [cell death].” (Salani, Barbara 2013)

Salani, Barbara, et al. “Metformin impairs glucose

consumption and survival in Calu-1 cells by direct
inhibition of hexokinase-II.” Scientific reports 3 (2013).
 Metformin – Synergy with DCA
“These data suggest that complex I
inhibition cooperates with DCA
activation of oxidative glucose
metabolism to promote catastrophic
oxidative stress in glioblastoma cells.
(Ward, 2017)
Ward, N. P., et al. “Complex I inhibition augments
dichloroacetate cytotoxicity through enhancing
oxidative stress in VM-M3 glioblastoma cells.” PloS one
12.6 (2017): e0180061.
Three Pillars of Cancer Cell Metabolism

Autophagy
© Copyright 2021 Jeffrey Dach MD
 Autophagy

Pro-survival mechanism in
cancer cells under
Trafficking (opposite

TQ, Mefloquine
HCQ, ChloroQ, Niclos
Racoma, Ira O., et al. "Thymoquinone inhibits autophagy and induces
cathepsin-mediated, caspase-independent cell death in glioblastoma cells."
PLoS One 8.9 (2013): e72882.
 “Protective Autophagy”
Many Anti-Cancer Drugs induce “Protective
Autophagy”.
Survival Mechanism. (Hibernation)
Activation AMPK/mTOR Inhibition induces
“Protective Autophagy”.
Perinuclear Clustering of Lysosomes (Dormant)
Antegrade Lysosome Trafficking (Aggressive)

Deng, Shuo, et al. "Targeting autophagy using natural compounds for cancer
prevention and therapy." Cancer 125.8 (2019): 1228-1246.
Kocaturk, Nur Mehpare, et al. "Autophagy as a molecular target for cancer
treatment." European Journal of Pharmaceutical Sciences 134 (2019): 116-
137.
 Peri-Nuclear Clustering
Top Row: Untreated
Breast Cancer Cells
showing lysosomes (dark
stained particles)
dispersed throughout
cells.

Bottom Row, Breast

cancer cells treated with
Artemisinin. Yellow
arrows point to peri-
nuclear clustering of
lysosomes.

Hamacher-Brady, Anne, et al.“Artesunate Activates Mitochondrial Apoptosis in Breast

Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production.” J. Biol.
Chem 2011.286 (2010): 6587-6601.
 Autophagy Inhibitors Push Cell Over
Apoptotic Threshold
Autophagy
Inhibitor Apoptosis
Cancer Cell

Apoptotic Threshold

Cell Death
Tompkins, K,"Focus: Death: Regulation of apoptosis by autophagy to enhance
cancer therapy." Yale journal of biology and medicine 92.4 (2019): 707.
© Copyright 2021 Jeffrey Dach MD
 Providing the Extra “Apoptotic Push”

“Autophagy inhibition works with many

different kinds of anti-cancer agents – it
doesn’t matter what the other drug is
so long as it is capable of providing an
extra pro-apoptotic push in that cancer
cell.” (Tompkins,2019)

Tompkins, Kenneth D., and Andrew Thorburn. "Focus: Death: Regulation of apoptosis by
autophagy to enhance cancer therapy." The Yale journal of biology and medicine 92.4
(2019): 707.
© Copyright 2021 Jeffrey Dach MD
 Autophagy Inhibitors
Mefloquine, Chloroquine, Hydroxy CHQ
Azithromycin/Clarithromycin (Doxy ?)
PPI’s
Loratidine (Claritin)
Thymoquinone (Black Seed Oil)
Propranolol (Dual OXPHOS/Autophagy)
Niclosamide (OXPHOS/Glycolysis/Autophagy)
Levy, Jean M. Mulcahy, Christina G. Towers, and Andrew Thorburn. "Targeting autophagy
in cancer." Nature Reviews Cancer 17.9 (2017): 528-542.
Deng, Shuo, et al. "Targeting autophagy using natural compounds for cancer prevention
and therapy." Cancer 125.8 (2019): 1228-1246.
Amaravadi, Ravi K., Alec C. Kimmelman, and Jayanta Debnath. "Targeting autophagy in
cancer: recent advances and future directions." Cancer discovery 9.9 (2019): 1167-1181.
Fourth Pillar

Restoring
Host
Immune
Surveillance

© Copyright 2021 Jeffrey Dach MD

Fifth Pillar Inflammation

Inhibit
NF-kB, IL-6
cytokines

© Copyright 2021 Jeffrey Dach MD

 SUMMARY SLIDE (1)
Eradicate Cancer Stem Cells
Cancer as a Metabolic Disease
Metabolic Derangements in Cancer Cells
GLYCOLYSIS (Warburg Effect) Cytoplasm
OXPHOS in Mitochondria
Autophagy
Detach HKII from VDAC (Itraconazole,
Fenofibrate)
Drugs and Supplements Targeting Pathways
 SUMMARY SLIDE (2)
DCA Synergy with OXPHOS inhibitors
(Metformin) and Autophagy Inhibitors
(Propranolol Both OXPHOS and Autophagy
Inhibitor)
Fourth Pillar – Restore Immune Surveillance
Fifth Pillar - Inflammation

© Copyright 2021 Jeffrey Dach MD

© Copyright 2021 Jeffrey Dach MD
Thank You – Any Questions?

TrueMedMD 7450 Griffin Road Suite 180/190 Davie, Fl 33314

954-792-4663 www.jeffreydachmd.com
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 Restoring Immune Surveillance
“The idea that the immune system, which
so effectively protects the host from
microbial pathogens, might also recognize
and destroy tumor cells was first discussed
over a century ago … tumor immune
surveillance, whereby the immune system
identifies cancerous and/or precancerous
cells and eliminates them before they can
cause harm. “ (Swann, 2007)
Swann, Jeremy B., and Mark J. Smyth. “Immune surveillance of tumors.” The Journal of
Clinical Investigation 117.5 (2007): 1137-1146.
 Restoring Immune Surveillance
Equal in Importance to ALL Three Pillars
Trophoblastic Theory (maternal-fetal tolerance)
and PIBF-evasion of the immune system, blocked
by Mifepristone (Alternate is Mebendazole).
The SR/CR Mouse (Spontaneous
Regression/Complete Resistance to cancer.)
Checkpoint Inhibitors, CAR-T Therapy
Coleys’s Toxins
Cimetidine
AHCC- Beta Glucans
Metformin, etc.
PIBF Progesterone Induced Blocking Factor
Both Placenta and Cancer to Escape Immune
Surveillance.
Pregnancy Lymphocytes secrete PIBF, allows
pregnancy to proceed withour rejection.
Cancer Cells Secrete PIBF, allows them to evade
immune system.
PIBF also stimulates Growth, Proliferation,
Aggressive Behavior.
Progesterone turns on PIBF production.
RU-486 (mifepristone) turns off PIBF production,
restoring immune competency.
PIBF Progesterone Induced Blocking Factor
PIBF associated with the Centrosome (spindle)
Mifepristone disrupts cytoskeleton, attenuates
the migration, movement, and invasion of cancer
cells, preventing metastatic disease.
Mifepristone synergy with chloroquine,
autophagy inhibitors.
Mifepristone restricted abortion drug
Mebendazole - Microtubule-disrupting drug
disturbs production of PIBF.
Use Mebendazole instead of Mifepristone?
Check, Jerome H., et al. "Treatment With Mifepristone Allows a Patient With End-stage
Pancreatic Cancer in Hospice on a Morphine Drip to Restore a Decent Quality of Life."
Anticancer Research 40.12 (2020): 6997-7001.
 Cimetidine - Tagamet
• Tagamet FDA-Approved 1979
• OTC Antacid- H2 Histamine Receptor Blocker
• Enhances Cell-Mediated Immunity.
• Reverses Histamine-Mediated Immunosuppression
• Induces IL-18 in monocytes- (immunostimulatory
cytokine with anti-tumor activity), promotes expansion
of NK Cells.
• Useful for: Cancer, Viral Warts, Recalcitrant
Urticaria, Interstitial Cytitis.
Pantziarka, Pan, et al. "Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer
agent." Ecancermedicalscience 8 (2014).
 AHCC - Beta Glucans
• Plant polysaccharides (sugars) found in edible
mushrooms, baker’s yeast, and cereals.
• (PAMPS) pathogen associated molecular patterns.
• Replacement for Coley’s Toxins ?
• Enhances Tumor Immune Surveillance.
• Eradicates HPV, has antiviral effects.

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

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):
 Other Immune Modulators
• Iodine for Breast Cancer Prevention and
Treatment, activation of the anti-tumoral
immune response, possible adjuvant in breast
cancer therapy. directly induces apoptosis in
cancer cells
• Vitamin D, steroid hormone immune modulator
• Probiotics, enhance checkpoint inhibitors,
prevent C Diff, reduces mortality in Allo
Transplant.
 Probiotics - 2017
Year of the Breakthrough
• “In 2017, epidemiological studies in humans
and experiments in mouse models showed
that the intestinal microbiota determines
the effectiveness of anti-cancer
immunotherapies.” (Kroemer ,2018)

Kroemer, Guido, and Laurence Zitvogel. “Cancer immunotherapy in 2017: The breakthrough
of the microbiota.” Nature Reviews Immunology 18.2 (2018): 87.
 Mebendazole
• Old Antiparasitic Drug.
• Microtubule inhibitor, prevents spindle formation
needed for cell replication.
• Immunomodulatory Effects – upregulates anti-
cancer host immune function.
• Link to PIBF ? Replacement for Mifepristone ?
• Induces Apoptosis by inactivating BCL-2
• Induces “Protective Autophagy”, Synergy with
Autophagy Inhibitors.
• Inhibits Hedgehog CSC pathway
Pantziarka, Pan, et al. "Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-
cancer agent." ecancermedicalscience 8 (2014).
Fifth Pillar Inflammation

Inhibit
NF-kB, IL-6
cytokines

© Copyright 2021 Jeffrey Dach MD

 COX-2 Inhibitors - Celecoxib

Stacpoole,
 CBD Cannabidiol
Detaches HKII from VDAC.
“Using microscale thermophoresis, we showed a
direct interaction between purified fluorescently
labeled VDAC1 and CBD.” (Rimmerman, 2013)
Potent Anti-inflammatory Effect
Immune Modulator
Rimmerman, N., et al. “Direct modulation of the outer mitochondrial membrane channel,
voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for
cannabinoid-induced cell death.” Cell death & disease 4.12 (2013): e949-e949.

Olivas-Aguirre, Miguel, et al. “Cannabidiol directly targets mitochondria and disturbs

calcium homeostasis in acute lymphoblastic leukemia.” Cell death & disease 10.10 (2019):
1-19.
 CBD targets VDAC Ca2+ Overload
CBD directly interacts with and switches VDAC to
a closed conformational substate . A similar
mechanism was also reported for curcumin and
aspirin and is considered to be the cause of the
tumor cell death
closed conformational is impermeable for large
metabolites like adenine nucleotides, but highly
permeable to Ca2+ [15]. The combination of
these two factors can eventually lead to
mitochondrial Ca2+ overload.(olivas,2021)
Olivas-Aguirre, Miguel, et al. "Phenolic Compounds Cannabidiol, Curcumin and Quercetin
Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells."
International Journal of Molecular Sciences 22.1 (2021): 204.
 Down Regulate Anti-Oxidant System
Solomons’s Seal
Auranofin (inhibits thioredoxin reductase
system),
Celecoxib Cox-2 inhibitor
Parthenolide (feverfew)
PQQ (pyrroloquinoline-quinine)
Sulfasalazine (Blocks Xct system cysteine uptake)
Sulforaphane (downreglulates intracellular
glutathione).

Stacpoole,
 Dipyridamole Anti-Platelet Agents
Sol

Stacpoole,
Financial Dislosure

None to Disclose
 Cancer Prevention
• Selenium
• Iodine
• Vitamin D3
• Di-Indole Methane (DIM)

Haider,
 LDN Low Dose Naltrexone
Opiate Receptor Blocker
Inhibits Tumor Growth

Stacpoole
 Case Report Targeting Cancer Stem Cells
Aggressivbe Aamous Cell CA 90 year old.
Fenofibrate
Itraconazole
Mebendazole
Exemestane
Doxycycline

Stacpoole,
 Alpha Lipoic Acid
Cofactor which Increases PDC Activity.
Shunts From Glycolysis to OXPHOS.
Restores Apoptosis.
Co-Factors are Thiamine, and Carnitine.
Synergy with Melatonin (Glycolysis
Inhibitor- Reverses Warburg Effect)

Bingham, Paul M. "Lipoic acid and lipoic acid analogs in cancer metabolism and
chemotherapy." Expert review of clin pharmacology 7.6 (2014): 837-846.
Berkson, Burton M. "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 ther 8.4 (2009): 416-422.
 Melatonin - Glycolysis Inhibitor
Sleep Hormone from Pineal Gland.
Reverses Warburg Effect via PDK inhibition.
Bacteria and Mitochondria Make Melatonin Acetyl-CoA.
Enters Cells via Glucose Transporters.
Accumulates in Cancer Cells.
Cancer Cell Mitochondria Lose ability to make Melatonin
Melatonin has a Decoupling Effect on OXPHOS.
Increases Electron Flow through ETC with Decoupling
Effect Causes Excess Damaging ROS… apoptosis in
cancer cells.

Pacini, Nicola, and Fabio Borziani. “Oncostatic-Cytoprotective Effect of Melatonin and

Other Bioactive Molecules: A Common Target in Mitochondrial Respiration.” International
journal of molecular sciences 17.3 (2016): 341.
 Melatonin and Cancer Stem Cells
“Thus, the treatment with melatonin and
the stimulation of mitochondrial
metabolism [i.e., with DCA] constitute
promising strategies against resistant CSCs.”
(Loureiro, Rute 2019)

Loureiro, Rute, et al. “Melatonin antiproliferative effects require active mitochondrial

function in embryonal carcinoma cells.” Oncotarget 6.19 (2015): 17081.
 Melatonin and Cancer Stem Cells

“Overall, the anti-cancer activity of

melatonin, combined with its actions via
multiple signaling pathways, is considered
hugely exciting to use this drug as a
possible treatment strategy to cure
cancer.” (Iravani, Shahrokh, 2019)

Iravani, Shahrokh, et al. “The Role of Melatonin in Colorectal Cancer.” Journal of

Gastrointestinal Cancer (2019): 1-6.
 Melatonin Synergy with DCA
Against Cancer Stem Cells
Degrades Beta-Catenin via activation of GSK3-
Beta
Prevents Transcription of Wnt Target Genes
Synergy with DCA against P19 Embryonal CSC
(only effective treatment )
DCA converts highly Glycolytic P19 cells to
OXPHOS
(OXPHOS) P19 cells are now sensitive to
Melatonin
Loureiro, Rute, et al. “Melatonin antiproliferative effects require active mitochondrial
function in embryonal carcinoma cells.” Oncotarget 6.19 (2015): 17081.