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Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin

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Summary

Cellular metabolic alterations are now well described as implicated in cancer and some strategies are currently developed to target these different pathways. In previous papers, we demonstrated that a combination of molecules (namely alpha-lipoic acid and hydroxycitrate, i.e. Metabloc™) targeting the cancer metabolism markedly decreased tumor cell growth in mice. In this work, we demonstrate that the addition of capsaicin further delays tumor growth in mice in a dose dependant manner. This is true for the three animal model tested: lung (LLC) cancer, bladder cancer (MBT-2) and melanoma B16F10. There was no apparent side effect of this ternary combination. The addition of a fourth drug (octreotide) is even more effective resulting in tumor regression in mice bearing LLC cancer. These four compounds are all known to target the cellular metabolism not its DNA. The efficacy, the apparent lack of toxicity, the long clinical track records of these medications in human medicine, all points toward the need for a clinical trial. The dramatic efficacy of treatment suggests that cancer may simply be a disease of dysregulated cellular metabolism.

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References

  1. Schwartz L, Abolhassani M, Guais A, Sanders E, Steyaert JM, Campion F, Israel M (2010) A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results. Oncol Rep 23:1407–1416. doi:10.3892/or_00000778

    Article  PubMed  CAS  Google Scholar 

  2. Abolhassani M, Guais A, Sanders E, Campion F, Fichtner I, Bonte Jacques, Baronzio G, Fiorentini G, Israel M, Schwartz L (2011) Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice. Invest New Drugs. doi:10.1007/s10637-011-9692-7, In press

  3. Israël M, Schwartz L (2011) The metabolic advantage of tumor cells. Mol Cancer 10:70. doi:10.1186/1476-4598-10-70

    Article  PubMed  Google Scholar 

  4. Warburg O (1956) On the origin of cancer cells. Science 123:309–14

    Article  PubMed  CAS  Google Scholar 

  5. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891. doi:10.1038/nrc1478

    Article  PubMed  CAS  Google Scholar 

  6. Bui T, Thompson B (2006) Cancer’s sweet tooth. Cancer Cell 9:419–20. doi:10.1016/j.ccr.2006.05.012

    Article  PubMed  CAS  Google Scholar 

  7. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ (2006) Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66:5216–5223. doi:10.1158/0008-5472.CAN-05-4193

    Article  PubMed  CAS  Google Scholar 

  8. Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25:4633–4646. doi:10.1038/sj.onc.1209597

    Article  PubMed  CAS  Google Scholar 

  9. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274:1393–1418. doi:10.1111/j.1742-4658.2007.05686.x

    Article  PubMed  CAS  Google Scholar 

  10. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS et al (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31ra34. doi:10.1126/scitranslmed.3000677

    Article  PubMed  CAS  Google Scholar 

  11. Berkson BM, Rubin DM, Berkson AJ (2006) The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integr Cancer Ther 5:83–89. doi:10.1177/1534735405285901

    Article  PubMed  Google Scholar 

  12. Berkson BM, Rubin DM, Rubin AJ (2009) Revisiting the alpha-LA/N (alpha-lipoic acid/low dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther 8:416–422. doi:10.1177/1534735409352082

    Article  PubMed  CAS  Google Scholar 

  13. Pardee TS, Levitan D, Hurd D (2011) Altered mitochondrial metabolism as a target in acute myeloid leukemia. ASCO Congress Poster

  14. Lee K, Khaira D, Rodriguez R, Maturo C, O’Donnell K, Shorr R (2011) Case study: long-term stable disease of stage IV pancreatic neuroendocrine tumors and without significant adverse effect by CPI-613, an investigational novel anti-cancer agent. Case Study Case Report 1:137–145

    Google Scholar 

  15. Guais A, Baronzio G, Sanders E, Campion F, Mainini C, Fiorentini G, Montagnani F, Behzadi M, Schwartz L, Abolhassani M (2012) Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumour development: experimental results and case report. Invest New Drugs 30:200–211. doi:10.1007/s10637-010-9552-x

    Article  PubMed  CAS  Google Scholar 

  16. Oberg K (2010) Antitumor effect of octreotide LAR, a somatostatin analog. Nature Rev Endocrinol 6:188–189. doi:10.1038/nrendo.2010.3

    Article  CAS  Google Scholar 

  17. Kang HJ, Soh Y, Kim MS, Lee EJ, Surh YJ, Kim HRC, Kim SH, Moon A (2003) Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells. Int J Cancer 103:475–482. doi:10.1002/ijc.10855

    Article  PubMed  CAS  Google Scholar 

  18. Ito K, Nakazato T, Yamato K, Miyakawa Y, Yamada T, Hozumi N, Segawa K, Ikeda Y, Kizaki M (2004) Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res 64:1071–1078. doi:10.1158/0008-5472.CAN-03-1670

    Article  PubMed  CAS  Google Scholar 

  19. Thoennissen NH, O’Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, Leiter A, Karlan B, Mehta R, Koeffler HP (2010) Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and –negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene 29:285–296. doi:10.1038/onc.2009.335

    Article  PubMed  CAS  Google Scholar 

  20. Choi CH, Jung YK, Oh SH (2010) Autophagy induction by capsaicin in malignant human breast cells is modulated by p38 and extracellular signal-related mitogen-activated protein kinases and retards cell death by suppressing endoplasmic reticulum stress-mediated apoptosis. Mol Pharmacol 78:114–125. doi:10.1124/mol.110.063495

    Article  PubMed  CAS  Google Scholar 

  21. Morré DJ, Chueh PJ, Morré DM (1995) Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Nat Acad Sci USA 92:1831–1835

    Article  PubMed  Google Scholar 

  22. Sanchez AM, Sanchez MG, Malagarie-Cauenave S, Olea N, Diaz-Laviada I (2006) Induction of apoptosis in prosstate tumor PC-3 cells and inhibitiion of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis 11:89–99. doi:10.1007/s10495-005-3275-z

    Article  PubMed  CAS  Google Scholar 

  23. Bhutani M, Pathak A, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal B (2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13:3024–3032. doi:10.1158/1078-0432.CCR-06-2575

    Article  PubMed  CAS  Google Scholar 

  24. Yang ZH, Wang XH, Wang HP, Hu LQ, Zheng XM, Li SW (2010) Capsaicin mediates death in bladder cancer T24 cells through reactive oxygen species production and mitochondrial polarization. Urology 75:735–741. doi:10.1016/j.urology.2009.03.042

    Article  PubMed  Google Scholar 

  25. Wang HM, Chueh PJ, Chang SP, Yang CL, Shao KN (2009) Effect of capsaicin on tNOX (ENOX2) protein expression in stomach cancer cells. Biofactors 34:209–217

    Article  Google Scholar 

  26. Nagy I, Santha P, Jancso G, Urban L (2004) The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology. Eur J Pharmacol 500:351–369. doi:10.1016/j.ejphar.2004.07.037

    Article  PubMed  CAS  Google Scholar 

  27. White JPM, Urban L, Nagy I (2011) TRPV1 function in health and disease. Curr Pharm Biotechnol 12:130–44

    Article  PubMed  CAS  Google Scholar 

  28. Mori A, Lehmann S, O’Kelly J, Kumagai T, Desmond JC, Pervan M, McBride WH, Kizaki M, Koeffler HP (2006) Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res 66:3222–3229. doi:10.1158/0008-5472.CAN-05-0087

    Article  PubMed  CAS  Google Scholar 

  29. Hail N Jr, Lotan R (2002) Examining the role of mitochondrial respiration in vanilloid-induced apoptosis. J Nat Cancer Inst 94:1281–1292. doi:10.1093/jnci/94.17.1281

    Article  PubMed  CAS  Google Scholar 

  30. Hail N Jr, Lotan R (2009) Cancer chemoprevention and mitochondria: targeting apoptosis in transformed cells via the disruption of mitochondrial bioenergenetics/redox state. Mol Nutr Food Res 53:49–67. doi:10.1002/mnfr.200700527

    Article  PubMed  CAS  Google Scholar 

  31. Wolvertang EJ, Larm JA, Moutsoulas P, Lawen A (1996) Apoptosis induced by inhibitors of the plasma membrane NADH-oxidase involves Bcl-2 and calcineurin. Cell Growth Differ 7:1315–1325

    Google Scholar 

  32. Macho A, Lucena C, Calzado MA, Blanco M, Donnay I, Appendino G, Munoz E (2000) Phorboid 20-homovanillates induce apoptosis through a VR1-independent mechanism. Chem Biol 7:483–492. doi:10.1016/S1074-5521(00)00132-0

    Article  PubMed  CAS  Google Scholar 

  33. Herst PM, Tan AS, Scarlett DG, Berridge MV (2004) Cell surface oxygen consumption by mitochondrial gene knockout cells. Biochim Biophys Acta 1656:79–87. doi:10.1016/j.bbabio.2004.01.008

    Article  PubMed  CAS  Google Scholar 

  34. Prata C, Grasso C, Loizzo S, Sega FVD, Caliceti C, Zambonin L, Fiorentini D, Hakim G, Berridge MV, Landi L (2010) Inhibition of trans-plasma membrane electron transport: a potential anti-leukemic strategy. Leuk Res 34:1630–1635. doi:10.1016/j.leukres.2010.02.032

    Article  PubMed  CAS  Google Scholar 

  35. Wilkinson F, Kim C, Cho N, Chueh PJ, Leslie S, Moya-Camarena S, Morré DM, Morré DJ (1996) Isolation and identification of a protein with capsaicin-inhibited NADH oxidase activity from culture media condition by growth of HeLa cells. Arch Biochem Biophys 336:275–282

    Article  PubMed  CAS  Google Scholar 

  36. Morré DJ, Caldwell S, Mayorga A, Wu LY, Morré DM (1997) NADH oxidase activity from sera altered by capsaicin is widely distributed among cancer patients. Arch Biochem Biophys 342:224–230

    Article  PubMed  Google Scholar 

  37. Chueh PJ (2000) Cell membrane redox systems and transformation. Antioxid Redox Signal 2:177–187

    Article  PubMed  CAS  Google Scholar 

  38. Chueh PJ, Wu LY, Morré DM, Morré DJ (2004) tNOX is both necessary and sufficient as a cellular target for the canticancer activity of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate. Biofactors 20:249–263

    CAS  Google Scholar 

  39. Morré DJ, Chueh PJ, Yagiz K, Balicki A, Kim C, Morré DM (2007) ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncol Res 16:299–312

    PubMed  Google Scholar 

  40. De Luca T, Morré DM, Zhao H, Morré DJ (2005) NAD+/NADH and/or CoQ/CoQH2 ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying G1 arrest and apoptosis. Biofactors 25:43–60

    Article  PubMed  Google Scholar 

  41. Sanchez AM, Malagarie-Cazenave S, Olea N, Vara D, Chileoches A, Diaz-Laviada I (2007) Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation. Apoptosis 12:2013–2024. doi:10.1007/s10495-007-0119-z

    Article  PubMed  CAS  Google Scholar 

  42. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58:262–270. doi:10.1016/j.phrs.2008.09.003

    Article  PubMed  CAS  Google Scholar 

  43. Bode AM, Dong Z (2011) The two faces of capsaicin. Cancer Res 71:2809–2814. doi:10.1158/0008-5472.CAN-10-3756

    Article  PubMed  CAS  Google Scholar 

  44. Surh YJ, Lee SS (1996) Capsaicin in hot chilli pepper: carcinogen, co-carcinogen or anticarcinogen. Food Chem Toxicol 34:314–316. doi:10.1016/0278-6915(95)00108-5

    Google Scholar 

  45. Chou CC, Wu YC, Wang YF, Chou MJ, Kuo SJ, Chen DR (2009) Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway. Oncol Rep 21:665–671. doi:10.3892/or_00000269

    PubMed  CAS  Google Scholar 

  46. Macho A, Sancho R, Minassi A, Appendino G, Lawen A, Munoz E (2003) Involvement of reactive oxygen species in capsaicinoid-induced apoptosis in transformed cells. Free Rad Res 37:611–619

    Article  CAS  Google Scholar 

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Acknowledgments

We acknowledge the help of Edward Sanders. The studies were performed by Nosco Pharmaceuticals (France). This work was funded by Biorébus.

Conflict of interest

METABLOC is a trade mark of Biorébus.

AG is an employee of Biorébus. The other authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Ecole Polytechnique, Laboratoire d’Informatique, Palaiseau, France

    Laurent Schwartz & Jean-Marc Steyaert

  2. AP-HP, Hôpital Raymond Poincaré, Service d’Oncologie, Garches, France

    Laurent Schwartz

  3. Biorébus, Paris, France

    Adeline Guais & Maurice Israël

  4. Formindep, Roubaix, France

    Bernard Junod

  5. METABLOC Cancer Center, Centro Medico Kines, Castano Primo, Milan, Italy

    Elisabetta Crespi & Gianfranco Baronzio

  6. Nosco Pharmaceuticals, Paris, France

    Mohammad Abolhassani

  7. Ecole Polytechnique Laboratoire LIX, 91128, Palaiseau, France

    Laurent Schwartz

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  1. Laurent Schwartz
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Correspondence to Laurent Schwartz.

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Supplementary Fig. 1

Summary statistics used when comparing outcomes between mice treated and not treated. Two statistics were used for analyzing in vivo tumor growth and response to treatment. Left - T/C%, the ratio of change over time in median tumor volume in percent for groups treated with capsaicin and for control groups; Right - Rp, the ratio dividing successes by failures of treatment with capsaicin across all possible pairs of mice, one coming from a treated group and the other from a control group. A ratio Rp = St/Ft lower than 1.0 would mean that the volume of the tumor is likely to increase more often in the treated group than in the control group (less successes than failures); a ratio larger than 1.0 would mean that the volume of the tumor is likely to increase less often in the treated group than in the control group (more successes than failures). The TVI (tumor volume increase) is obtained by subtracting the reference volume measured on the first day of treatment. (PDF 12 kb)

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Schwartz, L., Guais, A., Israël, M. et al. Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin. Invest New Drugs 31, 256–264 (2013). https://doi.org/10.1007/s10637-012-9849-z

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  • DOI: https://doi.org/10.1007/s10637-012-9849-z

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