Cancer as a Metabolic Disease

by Jeffrey Dach MD

Losing the War On Cancer

We have lost the war against cancer.  This becomes obvious by taking a quick look at the chart below.  Cancer Death Rates have declined slightly since 1975 due to reduction in lung cancer rates from decreased cigarette consumption.   Otherwise, there has been little change. Above left lung cancer cell dividing courtesy of NIH .  Below chart image courtesy of Scientific American.The Failure of Chemotherapy

In 1997, John C. Bailar M.D. explained how we lost the “War Against Cancer” : “The failure of chemotherapy to control cancer has become apparent even to the oncology establishment.”  

Here is a quote from  Dr. Haines in Lancet:  “The misplaced battlefield analogy has led to 40 years of toxic and overly aggressive chemotherapy in incurable solid cancers for which no studies have shown that maximum tolerated doses of chemotherapy achieve longer survival or better quality of life than do minimum effective doses. This approach has led to inappropriate and toxic therapies for many patients…. ”

Dr Carlos Garcia says cancer treatment with chemotherapy has a 97% failure rate: Three Per Cent Efficacy Of CHEMO On Cancer by Carlos Garcia MD.

Chemotherapy kills normal cells as well as cancer cells

The obvious flaw in cancer chemotherapy treatment is the non-specificity.  In other words, cancer chemotherapy kills cancer cells as well as normal cells.  This unwanted toxicity to normal cells accounts for the adverse side effects of chemotherapy, namely nausea, vomiting, loss of appetite, weight loss, bone marrow suppression with anemia, hair loss etc.

Finding a Selective Cancer Treatment, Leaving Normal Cells Unharmed

The optimal cancer treatment is one that kills cancer cells while leaving normal cells unharmed.  Dr Seyfried’s article, “Cancer as a metabolic disease ” points the way to this goal.(1)   Dr. Seyfried says: “cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation.“(1)  Electron microscope studies have shown abnormalities in the mitochondria of cancer cells.(2)  The cancer cell’s mitochondria have undergone “metabolic reprogramming”, thereby providing a key which can be exploited to devise a more selective cancer treatment. (3,4)  Above left image, Cover of book Cancer as a Metabolic Disease by Dr Thomas Seyfried courtesy of the Examiner. 

Drs Ko and Pederson, 3BP and Hexokinase II

Basic science studies by Drs Ko and Pedeson have uncovered the exact details of the metabolic reprogramming of the mitochondria of cancer cells.  In cancer cells, an embryonic form of Hexokinase called Hexokinase II has been attached to the membrane pores of the mitochondria (called VDAC voltage dependent anion channels) .  Hexokinase II is the first enzyme in glucose utilization and its location on the outer membrane pores allows for the massive utilization of glucose to feed the rapidly growing tumor mass.  Separation of the Hexokinase II from the VDAC pore on the outer mitochondrial membrane triggers apoptosis (programmed cell death) of the cancer cell while sparing normal cells.(5,6)

Above image: Dr. Young Ko and Dr. Peter Pedersen with Dr. Humaira Khan, Medicor CEO (left) and Dr. Akbar Khan Medicor Medical Director (right) at the Medicor Office in Toronto, December 2008. Courtesy of Medicor.

Discovery of 3BP by Dr. Ko

Drs Ko and Pederson discovered a small molecule called 3BP which throws a “monkey wrench” into the metabolic machinery of the cancer cell, and induces apoptosis via separation of Hexokinase II from the outer mitochondrial membrane. (7)(27, 28)

3BP (3 Bromo Pyruvate) is a small non-toxic molecule that induces apoptosis in cancer cells while sparing normal cells, thus providing the most promising cancer treatment we have seen in many years.  In-fighting over patent rights by the key players has delayed drug development and commercialization.  Unfortunately, 3BP as a cancer treatment may never come to fruition. (7)

Natural Compounds that Disassociate Hexokinase II from VDAC

Thankfully, there are many other compounds in the natural world that act on this same mechanism of selectively inducing apoptosis in cancer cells while sparing normal cells.   Many of these have already been commercialized and are available at the health food store.Left Image VDAC courtesy of NIH.

Resveratrol and Pterostilbenes

Resveratrol from grapes and its derivative Pterostilbene have been extensively studied and demonstrate striking anticancer activity.  Studies show that Pterostilbene induces apoptosis via the mitochondrial pathway in breast cancer cell lines. See the article by Moon.  Another article by Pei-Ching Hsiao.  His study used acute myeloid leukemia cells, finding pterostilbene induced apoptosis in cancer cells vIa mitochondrial pathways, (with activation of caspase system).  Another study by Alosi on Pterostilbene in Breast Cancer also showed similar findings with apoptosis induced by mitochondrial pathways.  Another more recent study by Wang in 2012 showed Pterostilbene induces apoptosis and cell cycle arrest in breast cancer cells.  See my previous article on this.

Abov image : electron microscope image of normal mitochondria courtesy of NIH.

Methyl Jasmonate

Methyl Jasmonate has been studied and found to disassociate Hexokinase II from the outer mitochondria membrane (at the VDAC) thus inducing apoptosis in cancer cells.  Methyl jasmonate is ubiquitous in the plant world and found in the jasmine flower.  It is used extensively by the fragrance industry for perfumes, and is available as one of many Jasmine teas.(8,9,10)

Oroxylin A  –  Chinese Skullcap

Oroxylin A is found in Chinese skullcap a medicinal plant, Scutellaria baicalensis Georgi.  Researchers found Oroxylin A inhibits glycolysis and the binding of hexokinase II (HK II) with mitochondria in human breast carcinoma cell lines, thus inducing apoptosis (11,12)

Curcumin

Curcumin was studied by Dr Wang in an animal model of colorectal cancer showing Curcumin inhibits aerobic glycolysis and induces mitochondrial-mediated apoptosis through hexokinase II in human colorectal cancer cells in vitro. (13)(31)  Curcumin is available at the health food store.

Betulinic acid

Betulinic acid naturally occurs in the bark of white birch trees and triggers mitochondrial apoptosis in cancer cells while sparing normal cells (14)  Dr, Simone Fulda from Ulm Germany has written a number of important papers on targeting mitochondria in cancer cells with various drugs and natural compounds.  (14,15)

See: Targeting_Mitochondria_Cancer_Therapy_Fulda_Nature_2010

Berberine – Oregon Grape

Berberine derived from the Oregon Grape plant is widely available as a botanical supplement at the health food store for blood sugar control.  Berberine also shows striking anti-cancer activity, inducing apoptosis via mitochondrial pathways in numerous studies.  Left Image Oregon Grape courtesy of wikimedia commons.(31,32)  See this 2014 review in Molecules,  Berberine as an “Epiphany Against Cancer“. (32)

Artemesinin (Chinese Wormwood)

An anti-malarial Chinese herb, artemesia, has been found to have profound anti-cancer activity against multiple cancer cell lines. Studies show induction of apoptosis through mitochondrial pathways. Approximately 400 studies have been published in the scientific literature in recent years.
Click on this link: Artemisinin_anti-Cancer_Publications, for the list of publications. Click on this link for an excellent review:
Artemisinins_Krishna_Trends_Pharmacological_Science_2008

Vitamin K

Vitamin K has been available for many years with heath benefits in blood coagulation, bone density, and prevention of soft tissue calcification.   See my previous article on Vitamin K.  Another surprising benefit of Vitamin K is cancer prevention.  A number of cell culture and animal xenograft studies shows that vitamin K2 induces apoptosis, programmed cell death, in cancer cells.(18-26)  There were a number of different cancers studied including Glioblastoma, Hepatocellular Cancer, Lung Cancer, Prostate Cancer, etc.(18-26)  Based on these reports, one might suggest adding Vitamin K  to a supplement program for anyone seeking to prevent cancer, or cancer recurrence after treatment.

Buy Pterostilbene on Amazon

Buy  Artemisininon Amazon

Buy Berberine  on Amazon

Buy Curcumin (Pure)

Buy Vitamin K (Synergy K)

Articles with related interest:

Nicholas Gonzalez and the Trophoblast Theory of Cancer

Iodine Treats Breast Cancer Overwhelming Evidence

Cannabis Oil Brain Tumor Remission

Natural Treatments for Skin Cancer

Addendum: Selectively killing cancer cells leaving normal cells unharmed – apoptosis through mitochondrial pathways

Mebendazole – Re purposing Old Drugs as Anti-Cancer Agents:

Researchers screened 2000 drugs currently approved for human use for anti-cancer activity against virulent melanoma cancer cell lines. They discovered mebenzadole as the most promising agent.   “Mebendazole treatment induces apoptosis through the intrinsic and extrinsic (mitochondrial) pathways in melanoma cells but not in melanocytes… After treatment with 0.5 μmol/L mebendazole for 14 h, we observed overall microtubular network disarray in melan-a, M-14, and SK-Mel-19 cells, characterized by diffuse staining” .(33-37)

See: mebendazole metastatic colon cancer Nygren Acta Oncologica 2014

See Anti- Cancer Agents in Fruits and Vegetables:
Molecular targets of dietary agents prevention cancer aggarwal 2006

Jeffrey Dach MD
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Davie, Fl 33314
954-792-4663

link to this article:http://wp.me/p3gFbV-2p8

Links and References

1) http://www.ncbi.nlm.nih.gov/pubmed/24343361
Carcinogenesis. 2014 Mar;35(3):515-27.
Cancer as a metabolic disease: implications for novel therapeutics.
Seyfried TN1, Flores RE, Poff AM, D’Agostino DP.
1Biology Department, Boston College, Chestnut Hill, MA 02467, USA and.

Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other 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.

Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies.

2) http://www.ncbi.nlm.nih.gov/pubmed/19703662
Int J Biochem Cell Biol. 2009 Oct;41(10):2062-8.
Electron microscopy morphology of the mitochondrial network in human cancer.
Arismendi-Morillo G.

Mitochondria have been implicated in the process of carcinogenesis, which includes alterations of cellular metabolism and cell death pathways. The aim of this review is to describe and analyze the electron microscopy morphology of the mitochondrial network in human cancer. The structural mitochondrial alterations in human tumors are heterogeneous and not specific for any neoplasm. These findings could be representing an altered structural and functional mitochondrial network. The mitochondria in cancer cells, independently of histogenesis, predominantly are seen with lucent-swelling matrix associated with disarrangement and distortion of cristae and partial or total cristolysis and with condensed configuration in minor scale. Mitochondrial changes are associated with mitochondrial-DNA mutations, tumoral microenvironment conditions and mitochondrial fusion-fission disequilibrium.

Functionally, the structural alterations suppose the presence of hypoxia-tolerant and hypoxia-sensitive cancer cells. Possibly, hypoxia-tolerant cells are related with mitochondrial condensed appearance and are competent to produce adequate amount of ATP by mitochondrial respiration. Hypoxia-sensitive cells are linked with lucent-swelling and cristolysis mitochondria profile and have an inefficient or null oxidative phosphorylation, which consequently use the glycolytic pathway to generate energy. Additionally, mitochondrial fragmentation is associated with apoptosis; however, alterations in the mitochondrial network are linked with the reduction in sensitivity to apoptosis induces and/or pro-apoptotic conditions. Pharmacological approaches designed to act on both glycolysis and oxidative phosphorylation can be considered as a new approach to selectively kill cancer cells.

3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311998/
Cancer Cell. Mar 20, 2012; 21(3): 297–308.
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Patrick S. Ward1,2 and Craig B. Thompson1,*

4) Tumor_Cell_Metabolism_Cancers_Achilles_Heel_Kroemer_2008
Cancer Cell  Volume 13, Issue 6, 10 June 2008, Pages 472–482
Tumor Cell Metabolism: Cancer’s Achilles’ Heel by  Guido Kroemer
Jacques Pouyssegur

Ko and Pederson

5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714668/
Semin Cancer Biol. Feb 2009; 19(1): 17–24.
Hexokinase-2 bound to mitochondria: Cancer’s stygian link to the “Warburg effect” and a pivotal target for effective therapy[star] Saroj P. Mathupala, Young H. Ko, and Peter L. Pedersen

6) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890051/
Biochim Biophys Acta. 2010 Jun–Jul; 1797(6-7): 1225–1230.
The Pivotal Roles of Mitochondria in Cancer: Warburg and Beyond and Encouraging Prospects for Effective Therapies
Saroj P. Mathupala,1 Young H. Ko,3 and Peter L. Pedersen*,2

7) http://www.thefreelibrary.com/War+on+cancer%3A+3BP+and+the+metabolic+approach+to+cancer%3A+a+visit+with…-a0332893717
Townsend Letter › June 1, 2013
War on cancer: 3BP and the metabolic approach to cancer: a visit with Peter Pedersen and Young Hee Ko

Methyl Jasmonate

8) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933403/
Int J Cell Biol. 2014; 2014: 572097.

Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis
Italo Mario Cesari,* Erika Carvalho, Mariana Figueiredo Rodrigues, Bruna dos Santos Mendonça, Nivea Dias Amôedo, and Franklin David Rumjanek
Laboratório de Bioquímica e Biologia Molecular do Câncer, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Prédio CCS, Bloco E, Sala 22, Ilha do Fundão, Cidade Universitária, 21941-902 Rio de Janeiro, RJ, Brazil

9) http://www.ncbi.nlm.nih.gov/pubmed/24490857

Br J Pharmacol. 2014 Feb;171(3):618-35. doi: 10.1111/bph.12501.
Methyl jasmonate sensitizes human bladder cancer cells to gambogic acid-induced apoptosis through down-regulation of EZH2 expression by miR-101.  Wang Y1, Xiang W, Wang M, Huang T, Xiao X, Wang L, Tao D, Dong L, Zeng F, Jiang G.

Gambogic acid (GA) and methyl jasmonate (MJ) are increasingly being recognized as novel natural anticancer compounds. Here, we investigated the antitumour effects of GA in combination with MJ on human bladder cancer cells.
EXPERIMENTAL APPROACH:Cell viability was detected by cell counting kit-8 assay. Cell apoptosis was assessed by Hoechst 33258 staining and flow cytometry. Protein levels were determined by immunoblotting and expressions of mRNA and miRNAs by RT-PCR. Differential expressions of a group of downstream genes were identified using microarray analysis.
KEY RESULTS:MJ significantly sensitized bladder cancer cells to GA-induced growth inhibition and apoptosis while sparing normal fibroblasts. MJ enhanced GA-induced activation of caspase-3 and caspase-9, and down-regulated the expression of XIAP. Furthermore, treatment of bladder cancer cells with a combination of GA and MJ induced synergistic inhibition of the enhancer of zeste homologue 2 (EZH2) expression, whereas miR-101 expression was up-regulated. Conversely, knockdown of miR-101 restored this decreased expression of EZH2 and suppressed the inhibitory effect of GA and MJ on the growth of bladder cancer cells. Microarray analysis showed that genes closely associated with bladder cancer development were significantly down-regulated by GA and MJ. In a s.c. xenograft mouse model of human bladder carcinoma, the combination of GA and MJ exerted an increased antitumour effect compared with GA alone.
CONCLUSION AND IMPLICATIONS:MJ sensitizes bladder cancer cells to GA-induced apoptosis by down-regulating the expression of EZH2 induced by miR-101. Thus, the combination of selective anti-cancer agents MJ and GA could provide a novel strategy for treating human bladder cancer.

10) http://www.phytotechlab.com/detail.aspx?ID=1176
METHYL JASMONATE Product ID: J389 Storage Temperature: 2 to 6°C
CAS Number: 39924-52-2

Description:  >95% Purity
Methyl Jasmonate (MeJA) is a key signaling hormone associated with necrotropic/herbivore stress which affects plant defense responses as well as growth and development
MeJA, 2-Pentenylcyclopentanone-3-acetic acid, Methyl 3-oxo-2-(pent-2-enyl)cyclopentaneacetate
Form: Liquid
Formula: C13H20O3
FW: 224.3
Solubility: Miscible with EtOH
Plant Tissue Culture Tested
Tariff Code: 2918.30.9000

BEFORE ORDERING PLEASE NOTE:
THIS PRODUCT, LIKE ALL PRODUCTS FROM PHYTOTECH LABS, IS FOR RESEARCH USE ONLY. WE CANNOT SELL TO CUSTOMERS WHO INTEND TO USE METHYL JASMONATE FOR HUMAN USE.

This product cannot be shipped to residential addresses; only shipments to bona fide research institutions and companies will be accepted.

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Oroxylin A

11) http://www.nature.com/cddis/journal/v4/n4/full/cddis2013131a.html
Cell Death and Disease (2013) 4, e601
Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma by L Wei1,2, Y Zhou1,2, Q Dai1, C Qiao1, L Zhao1, H Hui1, N Lu1 and Q-L Guo1
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, China Pharmaceutical University, Nanjing, The People’s Republic of China
Correspondence: Q-L Guo or N Lu, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, The People’s Republic of China.
Oroxylin A is a major active component of the Chinese traditional medicinal plant Scutellaria baicalensis Georgi, which has been reported as a potential anticancer drug. We demonstrated that, Oroxylin A inhibited the glycolysis and the binding of hexokinase II (HK II) with mitochondria in human breast carcinoma cell lines, which was dependent on sirtuin-3 (SIRT3). The level of SIRT3 in mitochondria was increased by Oroxylin A. Then SIRT3 deacetylated cyclophilin D, diminished its peptidyl-prolyl cis-trans isomerase activity and induced its dissociation from the adenine nucleotide translocator. Finally, SIRT3-induced inactivation of cyclophilin D resulted in the detachment of mitochondrial HK II and the inhibition of glycolysis. These results have important implications for the metabolism reprogramming effect and the susceptibility to Oroxylin A-induced mitochondrial cytotoxicity through the regulation of SIRT3 in breast carcinoma.

12) http://onlinelibrary.wiley.com/doi/10.1002/jcp.24833/abstract

Oroxylin A is a flavonoid extracted from the root of Scutellaria baicalensis Georgi. Our previous research demonstrated that oroxylin A have various anti-tumor effects including apoptosis, cell cycle arrest, drug-resistant reversion and others. This paper explores the mechanism how oroxylin A induce apoptosis by regulating uncoupling protein 2 (UCP2) in human colon cancer cells.

We found that the inhibition of UCP2 by UCP2 siRNA significantly increased the sensitivity of cells to drugs, reactive oxygen species (ROS) generation and the opening of mitochondrial permeability transition pore (MPTP) of CaCo-2 cells. We also found that UCP2 inhibition could lead to ROS-mediated MPTP activation. Furthermore, we demonstrated that oroxylin A triggered MPTP-dependent pro-apoptotic protein release from mitochondria to matrix and then induced apoptotic cascade by inhibiting UCP2. Intriguingly, the inhibition of UCP2 by oroxylin A was able to block Bcl-2 translocation to the mitochondria, keeping MPTP at open-state. In conclusion, we have demonstrate that UCP2 play a key role in mitochondrial apoptotic pathway; UCP2’s inhibition by oroxylin A triggers the MPTP opening, and promotes the apoptosis in CaCo-2 cells.

Curcumin

13) http://www.ncbi.nlm.nih.gov/pubmed/25229889
Anticancer Drugs. 2014 Sep 16. [Epub ahead of print] Curcumin inhibits aerobic glycolysis and induces mitochondrial-mediated apoptosis through hexokinase II in human colorectal cancer cells in vitro.
Wang K1, Fan H, Chen Q, Ma G, Zhu M, Zhang X, Zhang Y, Yu J.
1aJiangsu Institute of Cancer Research bJiangsu Research Institute of Geriatrics, Nanjing, China.

Curcumin, the major pigment of the dietary spice turmeric, has the potential for chemoprevention by promotion of apoptosis. Here, we investigated the molecular mechanisms of curcumin in glycolytic inhibition and apoptotic induction in human colorectal cancer HCT116 and HT29 cells. On the one hand, curcumin downregulated the expression and activity of hexokinase II (HKII) in HCT116 and HT29 cells in a concentration-dependent manner, but had little effect on the other key glycolytic enzymes (PFK, PGM, and LDH).

On the other, curcumin induced dissociation of HKII from the mitochondria, resulting in mitochondrial-mediated apoptosis. Furthermore, the phosphorylation of mitochondrial HKII through AKT was responsible for the curcumin-induced dissociation of HKII, which was different from the mechanism of HKII inhibitor 3-BrPA. These results have important implications for the metabolism reprogramming effect and the susceptibility to curcumin-induced mitochondrial cytotoxicity through the regulation of HKII, and provide a molecular basis for the development of naturally compounds as novel anticancer agents for colorectal carcinoma.

14) http://www.ncbi.nlm.nih.gov/pubmed/20486070
Planta Med. 2010 Aug;76(11):1075-9.
Modulation of apoptosis by natural products for cancer therapy.
Fulda S1. Children’s Hospital, Ulm University, Ulm, Germany.

15) Targeting_Mitochondria_Cancer_Therapy_Fulda_Nature_2010

Fulda, Simone, Lorenzo Galluzzi, and Guido Kroemer. “Targeting mitochondria for cancer therapy.” Nature reviews Drug discovery 9.6 (2010): 447-464.

Mitochondria are the cells’ powerhouse, but also their suicidal weapon store.
Dozens of lethal signal transduction pathways converge on mitochondria to cause the permeabilization of the mitochondrial outer membrane, leading to the cytosolic release of pro-apoptotic proteins and to the impairment of the bioenergetic functions of mitochondria.

The mitochondrial metabolism of cancer cells is deregulated owing to the use of  glycolytic  intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions. Activation of the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.

16) Mitochondrial_inhibitors_cancer_therapy_Pharmaceutical_Ramsay_2011 Ramsay, Emma E., Philip J. Hogg, and Pierre J. Dilda. “Mitochondrial metabolism inhibitors for cancer therapy.” Pharmaceutical research 28.11 (2011): 2731-2744.

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The War on Cancer A Progress Report for Skeptics
Reynold Spector . Volume 34.1, January / February 2010

War on Cancer SourceWatch

As War On Cancer Hits 25-Year Mark, Scientists See Progress, Challenges… It’s 25 years and counting since President Richard Nixon signed the National Cancer Act on Dec. 23, 1971, marking the United States’ official declaration of war on cancer. The act provided funding to establish medical centers dedicated to clinical research and cancer treatment under the auspices of the National Cancer Institute (NCI). Yet, after an estimated $28 billion spent to find cures and better treatments for the dreaded disease, the war is far from over. By Steven Benowitz | December 9, 1996

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