Cancer as a Metabolic Disease by Jeffrey Dach MD

Lung cancer cell division, SEM

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.War_On_Cancer_Lost_spector_cancer_Fig_22The 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

chemotherapy drugThe 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

Cancer As Metabolic Disease SeyfriedThe 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 Pederson 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)

Dr_Ko_Dr_Pedersen_Drs_KhanAbove 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 BromHuman_VDACo 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 and PterostilbeneResveratrol 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.Mitochondria

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

Methyl Jasmonate

MethylJasmonateMethyl 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)  Buy Jasmine Essential Oil on Amazon.

Oroxylin A  –  Chinese Skullcap

Oroxylin_A.svgOroxylin 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)(41-49)

Dr Huang studied Oroxylin A in a hepatoma cell model showing apoptosis through the mitochondrial pathway in human hepatoma HepG2 cells with activation of mitochondrial permeability transition pores.(41)  Chinese skullcap was also effective as an anti-cancer agent  in lung cancer, AML leukemia, and glioblastoma cell models.(41-49)

Penetrates into CNS and Concentrates in Brain.

Left image Baicalin in Chinese Skullcap . Note similarity with Oroxylin A. Image courtesy of Rx List.

Baicalin (Chinese Skullcap Root) penetrates into CNS according to Stephen Buhner’s book, and baicalin is concentrated in the brain, striatum,  thalamus and hippocampus (see page 137 Herbal Antivirals by Stephen Buhner).

Buy Chinese Skullcap Tincture at Elk Mountain

Buy Chinese Skullcap Capsules at Elk Mountain

Curcumin

640px-Curcumin_structure.svgCurcumin 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 Amazon  or the health food store.

Betulinic acid

Betulinic_acid_structureBetulinic 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) Betulinic Acid is available as a nutritional supplement (over the counter) called Chaga (capsules or tea). Above left chemical structure of Betulinic acid, note steroidal ring. Courtesy of Wikimedia.

Buy Chaga Gold 525mg by Aloha Medicinalson Amazon.

See: Betulinic acid induced tumor killing FB Müllauer 2011

See: Targeting_Mitochondria_Cancer_Therapy_Fulda_Nature_2010

640px-Berberine_acsv.svgBerberine – 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.

Oregon_Grape_Berberine_Jeffrey_Dach_MD

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 these links for an excellent review:
Artemisinins_Krishna_Trends_Pharmacological_Science_2008

Activation of Mitochondrial Driven Pathways by Artemesisin by Thomas Efferth

Vitamin K2

Vitamin K2 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 on Amazon

Buy Vitamin K2 (MK-7) on Amazon

Articles with related interest:

Artemisinin AntiCancer Gift From China

Ivermectin AntiCancer Drug

Cancer as a Parasitic Disease

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

MebendazoleRe 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 melanoma, M-14, and SK-Mel-19 cells, characterized by diffuse staining” .(33-37)

Usual dosage is 100 mg caps one cap twice a day.  Where to purchase mebendazole:
Ask for Brad at: Pavilion Compounding pharmacy
3193 Howell Mill Road NW , Suite 122A
Atlanta, GA 30327
(404) 350-5780

Also 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
7450 Griffin Road Suite 190
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.

——————————

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

Qiao, Chen, et al. “UCP2‐related mitochondrial pathway participates in oroxylin A‐induced apoptosis in human colon cancer cells.” Journal of cellular physiology (2014).

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.

17) Mitochondrial_permeability_target_anticancer_Dalla_2014  Dalla Via, Lisa, et al. “Mitochondrial permeability transition as target of anticancer drugs.” Current pharmaceutical design 20.2 (2014): 223-244.
———————————————–18) http://www.ncbi.nlm.nih.gov/pubmed/16400650
Cancer. 2006 Feb 15;106(4):867-72.
The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Mizuta T1, Ozaki I, Eguchi Y, Yasutake T, Kawazoe S, Fujimoto K, Yamamoto K. 1Department of Internal Medicine, Saga Medical School, Japan.19)http://www.ncbi.nlm.nih.gov/pubmed/23505456
PLoS One. 2013;8(3)  Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. Zhong JH1, Mo XS, Xiang BD, Yuan WP, Jiang JF, Xie GS, Li LQ. 1Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China.20)  http://www.ncbi.nlm.nih.gov/pubmed/16010434
Int J Oncol. 2005 Aug;27(2):505-11.
Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.
Kuriyama S1, Hitomi M, Yoshiji H, Nonomura T, Tsujimoto T, Mitoro A, Akahane21) http://www.ncbi.nlm.nih.gov/pubmed/15508263
Acta Neurol Belg. 2004 Sep;104(3):106-10.
Comparison of vitamins K1, K2 and K3 effects on growth of rat glioma and human glioblastoma multiforme cells in vitro. Oztopçu P1, Kabadere S, Mercangoz A, Uyar R. 1Osmangazi University Art and Sciences Faculty Department of Biology, Eskişehir, Türkiye.22) http://www.ncbi.nlm.nih.gov/pubmed/19424596
Int J Mol Med. 2009 Jun;23(6):709-16.
Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis.  Kawakita H1, Tsuchida A, Miyazawa K, Naito M, Shigoka M, Kyo B, Enomoto M, Wada T, Katsumata K, Ohyashiki K, Itoh M, Tomoda A, Aoki T.  1Third Department of Surgery, Tokyo Medical University, Tokyo, Japan.
23) http://www.ncbi.nlm.nih.gov/pubmed/12888897
Int J Oncol. 2003 Sep;23(3):627-32.
Apoptosis induction of vitamin K2 in lung carcinoma cell lines: the possibility of vitamin K2 therapy for lung cancer.  Yoshida T1, Miyazawa K, Kasuga I, Yokoyama T, Minemura K, Ustumi K, Aoshima M, Ohyashiki K.      1First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.24) http://www.ncbi.nlm.nih.gov/pubmed/19929921
J Gastroenterol Hepatol. 2010 Apr;25(4):738-44. doi: 10.1111/j.1440-1746.2009.06085.x. Epub 2009 Nov 19. Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway. Showalter SL1, Wang Z, Costantino CL, Witkiewicz AK, Yeo CJ, Brody JR, Carr BI.     1Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.25) http://www.ncbi.nlm.nih.gov/pubmed/17611688
Int J Oncol. 2007 Aug;31(2):323-31.
Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.  Ogawa M1, Nakai S, Deguchi A, Nonomura T, Masaki T, Uchida N, Yoshiji H, Kuriyama S.26) http://www.ncbi.nlm.nih.gov/pubmed/23875252
Pharmazie. 2013 Jun;68(6):442-8.
Vitamin K4 induces tumor cytotoxicity in human prostate carcinoma PC-3 cells via the mitochondria-related apoptotic pathway.
Jiang Y1, Yang J, Yang C, Meng F, Zhou Y, Yu B, Khan M, Yang H.
1School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, PR China.27) Inhibitory effects of 3-bromopyruvate on human gastric cancer implant tumors in nude mice_Shu-Lin XianXian, Shu-Lin, et al. “.” Asian Pacific journal of cancer prevention: APJCP 15.7 (2014): 3175.28) Chen, Zhao, et al. “Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate.” Biochimica et Biophysica Acta (BBA)-Bioenergetics 1787.5 (2009): 553-560.Jasmonate pharmaceutical composition for treatment of cancer
United States Patent 6469061
Inventors:
Flescher, Eliezer (Hod Hasharon, IL)
Fingrut, Orit (Kfar-Sava, IL)
Application Number: 09/825347
Publication Date: 10/22/2002
Filing Date: 04/04/200130) Methyl Jasmonate: A New Treatment for B-CLL?.
Alain Berrebi, MD1, Lucette Bassous1,*, Rinat Borenshtain, PhD2,* and Eliezer Flescher, PhD3,*  1 Hematology, Kaplan Medical Center, Rehovot, Israel; 2 Sepal Pharma, Nes Ziona, Israel and 3 Immunology, Tel Aviv University, Tel Aviv, Israel.CEO Dr. Frederic Revah, PhDSepal Pharma, Nes Ziona
Registered Office P.O.Box: 333
Ness Ziona, 74103  Israel
Tel. 08-9302088
Web Site http://www.sepalpharma.com31) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693477/Aggarwal, Bharat, et al. “Prevention and treatment of colorectal cancer by natural agents from Mother Nature.” Current colorectal cancer reports 9.1 (2013): 37-56.

32) http://www.mdpi.com/1420-3049/19/8/12349/htm

Guamán Ortiz, Luis Miguel, et al. “Berberine, an Epiphany Against Cancer.” Molecules 19.8 (2014): 12349-12367.

Anti-Parasitic Drug Vermox  (mebendazole)

33) mebendazole metastatic colon cancer Nygren Acta Oncologica 2014

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): 427-428.

34) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/
Pantziarka, Pan et al. “Repurposing Drugs in Oncology (ReDO)—mebendazole as an Anti-Cancer Agent.” ecancermedicalscience 8 (2014): 443. PMC. Web. 13 Jan. 2015.

35)http://mcr.aacrjournals.org/content/6/8/1308.full

Doudican, Nicole, et al. “Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells.” Molecular Cancer Research 6.8 (2008): 1308-1315.

36)  http://neuro-oncology.oxfordjournals.org/content/early/2011/07/14/neuonc.nor077.full   Bai, Ren-Yuan, et al. “Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme.” Neuro-oncology (2011): nor077.

37)Mebendazole metastatic adrenocortical carcinoma Dobrosotskaya Endocrine practice 2011 Dobrosotskaya, I. Y., et al. “Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma.” Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 17.3 (2011): e59.

38) Betulinic acid induced tumor killing FB Müllauer 2011

39) Targeting_Mitochondria_Cancer_Therapy_Fulda_Nature_2010

40) Resveratrol_derivatives_cancer_Drug_Discov_Today_2010_Fulda

Chinese Skullcap Oroxylyn A

41) Huang, Xin-Eng, et al. “MPTP related mitochondrial pathway in oroxylin A induced-apoptosis in HepG2 cancer cells.” Int J Clin Exp Pathol 9.11 (2016): 11139-11148. oroxylin A induced apoptosis in cancer cells Huang Int J Clin Exp Pathol 2016

42) Wei, Libin, et al. “Oroxylin A sensitizes non-small cell lung cancer cells to anoikis via glucose-deprivation-like mechanisms: c-Src and hexokinase II.” Biochimica et Biophysica Acta (BBA)-General Subjects 1830.6 (2013): 3835-3845.

43) Hui, Hui, et al. “Oroxylin A has therapeutic potential in acute myelogenous leukemia by dual effects targeting PPARγ and RXRα.” International journal of cancer 134.5 (2014): 1195-1206.

44) Lee, D. H., et al. “Wogonin induces apoptosis by activating the AMPK and p53 signaling pathways in human glioblastoma cells.” Cellular signalling 24.11 (2012): 2216.

baicalein – chinese skullcap

45)  Gao, Ying, et al. “Anticancer properties of baicalein: a review.” Medicinal Chemistry Research 25.8 (2016): 1515-1523.

46) Chen, Haijun, et al. “Exploring therapeutic potentials of baicalin and its aglycone baicalein for hematological malignancies.” Cancer letters 354.1 (2014): 5-11.

Several studies have demonstrated that S. baicalensis, baicalin and baicalein display antiproliferative and apoptotic effects against lymphoma [17,54,55]. Huang et al. reported that baicalin is capable of suppressing the growth of CA46 Burkitt lymphoma cells via induction of apoptosis with an IC50 value of 10 μM [56]. In addition, baicalin almost completely inhibits colony formation at 10 μM. CA46 cells undergo apoptosis in response to baicalin induced apoptosis via up-regulating the cleaved forms of caspase-9, caspase-3, and PARP. Furthermore, baicalin is capable of downregulating antiapoptotic and upregulating apoptotic components of the PI3K/Akt signaling pathway [56].

47) Chen YJ, Wu CS, Shieh JJ, Wu JH, Chen HY, Chung TW, Chen YK, Lin CC (2013c) Baicalein triggers mitochondria-mediated apoptosis and enhances the antileukemic effect of vincristine in childhood acute lymphoblastic leukemia CCRF-CEM cells. Evid Based Complementary Altern Med 2013:124747…..we found a synergistic therapeutic effect when baicalein and vincristine were used in combination.

48)   J Ethnopharmacol. 2012 Jun 1;141(2):742-53. doi: 10.1016/j.jep.2011.08.042. Epub 2011 Aug 26.
In vitro and in situ evaluation of herb-drug interactions during intestinal metabolism and absorption of baicalein.
Fong YK1, Li CR, Wo SK, Wang S, Zhou L, Zhang L, Lin G, Zuo Z.

Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (-)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models.
MATERIALS AND METHODS:Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose-response curves were plotted and IC(50) values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb-drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples.
RESULTS:It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites.
CONCLUSIONS:Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb-drug and herb-herb interactions between B and selected compounds, especially CUR.

49) J Ethnopharmacol. 2014 Oct 28;156:210-5. doi: 10.1016/j.jep.2014.08.031. Epub 2014 Sep 8.Safety, tolerability, and pharmacokinetics of a single ascending dose of baicalein chewable tablets in healthy subjects.Li M1, Shi A2, Pang H1, Xue W1, Li Y1, Cao G1, Yan B1, Dong F1, Li K1, Xiao W3, He G4, Du G4, Hu X1.
The root of Scutellaria baicalensis Georgi has been used extensively in traditional Chinese medicine for the treatment of inflammation, fever, cough, dysentery, and hypertension. Baicalein is a flavonoid isolated from the root of Scutellaria baicalensis Georgi and is a novel neuroprotective agent under development for the treatment of Parkinson׳s disease. We aimed to investigate the pharmacokinetic (PK) properties of baicalein and its main metabolite, bacalin, after single-dose administration in healthy Chinese subjects. The safety and tolerability of baicalein were also assessed.
MATERIALS AND METHODS:

This was a Phase I, randomized, double-blind, single-dose trial of baicalein (100-2800 mg) in 72 healthy adults. Samples of blood, urine and feces were collected at regular intervals up to 48 h after administration of the study drug. Baicalein and baicalin were then analyzed using liquid chromatography-tandem mass spectrometry (LC/MS/MS). The maximum concentration that the drug achieved after dosing (Cmax), time to Cmax (Tmax), terminal half-life (t₁/₂), area under the curve from time zero to time of last quantifiable concentration (AUC(0, t)), area under the curve from time zero to infinity (AUC(0, ∞)), apparent total plasma clearance (CL/F), and apparent total volume of distribution (V/F) were determined using non-compartmental models. Dose proportion was tested using a method combining the equivalence criterion and power model. Physical examinations, vital signs, ECG findings, hematology, and urinalysis were monitored before and at regular intervals after administration of the study drug.
RESULTS:

The PK profile of baicelein and baicelin was characterized by a median Tmax of 0.75-3.5 h and 0.5-3 h, respectively, followed by a multiphasic profile with a t₁/₂ of 1.90-15.01 h and 4.22-10.80 h, respectively. The estimates of the proportionality coefficient (90% CI) for Cmax, AUC₀-t and AUC₀-∞ were 0.83 (0.70-0.96), 0.91 (0.81-1.00) and 0.92 (0.82-1.02), respectively. All values overlapped within the pre-specified range of (0.89-1.11), (0.93-1.07), and (0.93-1.07), respectively. Dose proportionality was inconclusive for a baicalein dose range of 100-2800 mg. The total urinary clearance of baicalein and baicalin was <1%. Approximately 27% of baicalein was eliminated as unchanged drug in feces. Baicalein was well tolerated. Eleven treatment-related adverse events were observed, and all were rated as “mild” and resolved without further treatment. No serious adverse events occurred.
CONCLUSIONS:

Single oral doses of 100-2800 mg of baicalein were safe and well tolerated by healthy subjects. Clinical laboratory assessments showed no signs of toxicity in the liver or kidney. The favorable safety profile and PK properties warrant further clinical studies for baicalein.

50)  Orzechowska, B., et al. “Baicalin from the extract of Scutellaria baicalensis affects the innate immunity and apoptosis in leukocytes of children with acute lymphocytic leukemia.” International Immunopharmacology 23 (2014): 558-567.

51)  Ma, Xingcong, et al. “Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/β-catenin pathway.” Drug design, development and therapy 10 (2016): 1419.

Our results demonstrate that baicalein has the potential to suppress breast cancer metastasis, possibly by inhibition of EMT, which may be attributed to downregulation of both SATB1 and the Wnt/β-catenin pathway. Taken together, baicalein may serve as a promising drug for metastasis treatment of breast cancer.

52) Gasiorowski, K., et al. “Flavones from root of Scutellaria baicalensis Georgi: drugs of the future in neurodegeneration?.” CNS & neurological disorders drug targets 10.2 (2011): 184.
Abstract

Flavonoids are natural, plant-derived compounds which exert diverse biological activities, also valuable neuroprotective actions within the brain and currently are intensively studied as agents able to modulate neuronal function and to prevent age-related neurodegeneration. Among them, flavones isolated from Scutellaria baicalensis root exhibit strong neuroprotective effects on the brain and are not toxic in the broad range of tested doses. Their neuroprotective potential has been shown in both oxidative stress-induced and amyloid-beta and alpha-synuclein-induced neuronal death models. Baicalein, the main flavone present in Scutellaria baicalensis root, strongly inhibited aggregation of neuronal amyloidogenic proteins in vitro and induces dissolution of amyloid deposits. It exerts strong antioxidative and anti-inflammatory activities and also exhibits anti-convulsive, anxiolytic, and mild sedative actions. Importantly, baicalein, and also another flavone: oroxylin A, markedly enhanced cognitive and mnestic functions in animal models of aging brains and neurodegeneration. In the preliminary study, wogonin, another flavone from Scutellaria baicalensis root, has been shown to stimulate brain tissue regeneration, inducing differentiation of neuronal precursor cells. This concise review provides the main examples of neuroprotective activities of the flavones and reveals their potential in prevention and therapyof neurodegenerative diseases.

53)   Evid Based Complement Alternat Med. 2013;2013:124747.
Baicalein Triggers Mitochondria-Mediated Apoptosis and Enhances the Antileukemic Effect of Vincristine in Childhood Acute Lymphoblastic Leukemia CCRF-CEM Cells.  Chen YJ1, Wu CS, Shieh JJ, Wu JH, Chen HY, Chung TW, Chen YK, Lin CC.
Acute lymphoblastic leukemia (ALL) accounts for approximately 75% of childhood leukemia, and chemotherapy remains the mainstay therapy. Baicalein is an active flavonoid used in traditional Chinese medicine and has recently been found to have anticancer, anti-inflammatory, and antiallergic properties. This study aims to investigate the molecular apoptotic mechanisms of baicalein in CCRF-CEM leukemic cells and to evaluate the combined therapeutic efficacy of baicalein with several commonly used chemotherapeutic drugs in CCRF-CEM cells. Our results demonstrate that baicalein induces mitochondria-dependent cleavage of caspases-9 and -3 and PARP with concomitant decreases in IAP family proteins, survivin, and XIAP. Furthermore, our results present for the first time that baicalein triggers a convergence of the intrinsic and extrinsic apoptotic pathways via the death receptor-caspase 8-tBid signaling cascade in CCRF-CEM cells. In addition, we also present for the first time that the combination of baicalein and vincristine results in a synergistic therapeutic efficacy. Overall, this combination strategy is recommended for future clinical trials in the treatment of pediatric leukemia owing to baicalein’s beneficial effects in alleviating the vomiting, nausea, and skin rashes caused by chemotherapy.

54) Biomolecules & Therapeutics, 16, 343-350(2008)
The Scutellaria Flavone, Oroxylin A, Improves Attention-Deficit/
Hyperactivity Disorder Related Behaviors in Spontaneously
Hypertensive Rats  Oroxylin A improves attention deficit hyperactivity disorder in rats Yoon Seo Young Biomolecules Therapeutics 2008
Seo Young YOON5, Mi Sook CHUN5, Yong Soo LEE1, Hae Il PARK2, Chan Young SHIN3, Jong Hoon RYU4, and Jae Hoon CHEONG*
Uimyung Institute for Neuroscience, Sahmyook University, Seoul 139-742, Republic of Korea

55) Yoon, Seo Young, et al. “Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro.” Archives of pharmacal research 36.1 (2013): 134-140. Oroxylin A improves attention deficit hyperactivity disorder rat inhibits reuptake dopamine Yoon Seo Young Archives pharmacal research 2013

——————————————

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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Cancer as a Metabolic Disease by Jeffrey Dach MD
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Cancer as a Metabolic Disease by Jeffrey Dach MD
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Cancer as a Metabolic Disease by Jeffrey Dach MD
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Jeffrey Dach MD