Investigational New Drugs

, Volume 30, Issue 1, pp 200–211

Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumor development: experimental results and case report

  • Adeline Guais
  • GianFranco Baronzio
  • Edward Sanders
  • Frédéric Campion
  • Carlo Mainini
  • Giammaria Fiorentini
  • Francesco Montagnani
  • Mahsa Behzadi
  • Laurent Schwartz
  • Mohammad Abolhassani
PRECLINICAL STUDIES

Summary

Altered metabolism of cancer first highlighted by Otto Warburg has a long history. Although ignored for a considerable amount of time, it is now receiving substantial attention. We recently published results obtained with a combination of two drugs, lipoic acid and hydroxycitrate, targeting metabolic enzymes particularly affected in cancer: ATP citrate lyase and pyruvate dehydrogenase kinase. This treatment was as efficient as chemotherapy in the three mouse cancer models that were tested. In this work, we asked if our drug combination could be used in conjunction with standard cytotoxic chemotherapy, in particular cisplatin, to improve basic protocol efficacy. A combination of lipoic acid and hydroxycitrate was administered to mice implanted with syngeneic cancer cells, LL/2 lung carcinoma and MBT-2 bladder carcinoma, concommitantly with classical chemotherapy (cisplatin or methotrexate). We demonstrate that the triple combination lipoic acid + hydroxycitrate + cisplatin or methotrexate is more efficient than cisplatin or methotrexate used individually or the combination of lipoic acid and hydroxycitrate administered alone. Of particular note are the results obtained in the treatment of an 80 year-old female who presented with ductal adenocarcinoma of the pancreas accompanied by liver metastases. A treatment course using gemcitabine plus α-lipoic acid and hydroxycitrate gave highly promising results. The in vivo data, coupled with the case study results, suggest a possible advantage in using a treatment targeted at cancer metabolism in association with classical chemotherapy.

Keywords

Metabolic therapy Pyruvate dehydrogenase ATP citrate lyase 

Supplementary material

10637_2010_9552_MOESM1_ESM.doc (40 kb)
Supplementary Table 1(DOC 39 kb)
10637_2010_9552_MOESM2_ESM.doc (34 kb)
Supplementary Table 2(DOC 33 kb)
10637_2010_9552_MOESM3_ESM.doc (34 kb)
Supplementary Table 3(DOC 33 kb)

References

  1. 1.
    Warburg O (1956) On the origin of cancer cells. Science 123:309–314PubMedCrossRefGoogle Scholar
  2. 2.
    Vander Heiden MG, Cantley LC, Thompson CG (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. doi:10.1126/science.1160809 PubMedCrossRefGoogle Scholar
  3. 3.
    Gambhir SS, Czernin J, Schwimmer J, Silverman DHS, Coleman RE, Phelphs ME (2001) A tabulated summary of the FDG PET literature. J Nucl Med 42:1S–93SPubMedGoogle Scholar
  4. 4.
    Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482. doi:10.1016/j.ccr.2008.05.005 PubMedCrossRefGoogle Scholar
  5. 5.
    Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899. doi:10.1038/nrc1478 PubMedCrossRefGoogle Scholar
  6. 6.
    López-Lázaro M (2008) The warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem 8:305–312PubMedCrossRefGoogle Scholar
  7. 7.
    Pederson PL (2007) Warburg, me and hexokinase 2: multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembranes 39:211–222. doi:10.1007/s10863-007-9094-x CrossRefGoogle Scholar
  8. 8.
    Mazurek S (2008) Pyruvate kinase type M2: a key regulator within the tumour metabolome and a tool for metabolic profiling of tumors. Ernst Schering Found Symp Proc 4:99–124CrossRefGoogle Scholar
  9. 9.
    Dang CV (2007) The interplay between MYC and HIF in the Warburg effect. Ernest Schering Found Symp Proc 4:35–53CrossRefGoogle Scholar
  10. 10.
    Hatzivassiliou G, Zhao F, Bauer D, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB (2005) ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8:311–321. doi:10.1016/j.ccr.2005.09.008 PubMedCrossRefGoogle Scholar
  11. 11.
    Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51. doi:10.1016/j.ccr.2006.10.020 PubMedCrossRefGoogle Scholar
  12. 12.
    Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S, Urbanek C, Rosser CJ (2008) Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68:1223–1231. doi:10.1002/pros.20788 PubMedCrossRefGoogle Scholar
  13. 13.
    Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol 109:394–402. doi:10.1016/j.ygyno.2008.01.038 PubMedCrossRefGoogle Scholar
  14. 14.
    Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260. doi:10.1007/s10549-009-0435-9 PubMedCrossRefGoogle Scholar
  15. 15.
    Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994. doi:10.1038/sj.bjc.6604554 PubMedCrossRefGoogle Scholar
  16. 16.
    Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31ra34. doi:10.1126/scitranslmed.3000677 PubMedCrossRefGoogle Scholar
  17. 17.
    Tennant DA, Durán RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10:267–277. doi:10.1038/nrc2817 PubMedCrossRefGoogle Scholar
  18. 18.
    Schwartz L, Abolhassani M, Guais A, Sanders E, Steyaert JM, Campion F, Israël 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 PubMedCrossRefGoogle Scholar
  19. 19.
    Savage P, Stebbing J, Bower M, Crook T (2009) Why does cytotoxic chemotherapy cure only some cancers? Nat Clin Pract Oncol 6:43–52. doi:10.1038/ncponc1260 PubMedCrossRefGoogle Scholar
  20. 20.
    Tomayko MM, Reynolds CP (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24:148–154PubMedCrossRefGoogle Scholar
  21. 21.
    Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942. doi:10.1172/JCI36843 PubMedGoogle Scholar
  22. 22.
    Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–1080. doi:10.1126/science.1164097 PubMedCrossRefGoogle Scholar
  23. 23.
    Padhye S, Ahmad A, Oswal N, Sarkar FH (2009) Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. J Hematol Oncol 2:38PubMedCrossRefGoogle Scholar
  24. 24.
    Akao Y, Nakagawa Y, Iinuma M, Nozawa Y (2008) Anti-cancer effects of xanthones from pericarps of mangosteen. Int J Mol Sci 9:355–370PubMedCrossRefGoogle Scholar
  25. 25.
    Havelka AM, Berndtsson M, Olofsson MH, Shoshan MC, Linder S (2007) Mechanisms of action of DNA-damaging anticancer drugs in treatment of carcinomas: is acute apoptosis an “off-target” effect? Mini-Rev Med Chem 7:1035–1039PubMedCrossRefGoogle Scholar
  26. 26.
    Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev 99:2467–2498PubMedCrossRefGoogle Scholar
  27. 27.
    Cepeda V, Fuertes MA, Castilla J, Alonso C, Quefedo C, Perez JM (2007) Biochemical mechanisms of cisplatin cytotoxicity. Anticancer Agents Med Chem 7:3–18PubMedCrossRefGoogle Scholar
  28. 28.
    Cullen KJ, Yang Z, Schumaker L, Guo Z (2007) Mitochondria as a critical target of the chemotherapeutic agent cisplatin in head and neck cancer. J Bioenerg Biomembr 39:43–50. doi:10.1007/s10863-006-9059-5 PubMedCrossRefGoogle Scholar
  29. 29.
    Fisch MJ, Howard KL, Einhorn LH, Sledge GW (1996) Relationship between platinum-DNA adducts in leukocytes of patients with advanced germ cell cancer and survival. Clin Cancer Res 2:1063–1066PubMedGoogle Scholar
  30. 30.
    Volpato JP, Fossati E, Pelletier JN (2007) Increasing methotrexate resistance by combination of active-site mutations in human dihydrofolate reductase. J Mol Biol 373:599–611PubMedCrossRefGoogle Scholar
  31. 31.
    Li JC, Kaminskas E (1984) Accumulation of DNA strand breaks and methotrexate cytoxicity. Proc Nat Acad Sci USA 81:5694–5698. doi:10.1016/j.jmb.2007.07.076 PubMedCrossRefGoogle Scholar
  32. 32.
    Celtikici B, Lawrance AK, Wi Q, Rozen R (2009) Methotrexate-induced apoptosis is enhanced by altered expression of methylenetrahydrofolate reductase. Anti-Cancer Drugs 20:787–793. doi:10.1097/CAD.0b013e32832f4aa8 CrossRefGoogle Scholar
  33. 33.
    Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, Wheeler S, Swart AM, Qian W, Torri V, Floriani I, Jayson G, Lamont A, Tropè C, ICON and AGO Collaborators (2003) Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 36:2099–2106. doi:10.1016/S0140-6736(03)13718-X Google Scholar
  34. 34.
    Horwitz SB (1992) Mechanism of action of taxol. Trends Pharmacol Sci 13:134–136PubMedCrossRefGoogle Scholar
  35. 35.
    Haldar S, Jena N, Croce CM (1995) Inactivation of Bcl-2 by phosphorylation. Proc Nat Acad Sci USA 92:4507–4511PubMedCrossRefGoogle Scholar
  36. 36.
    Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer H-R, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schuelere A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127PubMedCrossRefGoogle Scholar
  37. 37.
    Chou AJ, Geller DS, Gorlick R (2008) Therapy for osteosarcoma: where do we go from here? Pediatr Drugs 10:315–327CrossRefGoogle Scholar
  38. 38.
    Ferrari S, Palmerini E (2007) Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma. Curr Opin Oncol 19:341–346. doi:10.1097/CCO.0b013e328122d73f PubMedCrossRefGoogle Scholar
  39. 39.
    Van Dalen EC, de Camargo B (2009) Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane Database Syst Rev 1:CD006325. doi:10.1002/14651858.CD006325.pub2 PubMedGoogle Scholar
  40. 40.
    Teachey DT, Sheen C, Hall J, Ryan T, Brown VI, Fish J, Reid GSD, Seil AE, Norris R, Chang YJ, Carroll M, Grupp SA (2008) mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood 112:2020–2023. doi:10.1182/blood-2008-02-137141 PubMedCrossRefGoogle Scholar
  41. 41.
    Casneuf FV, Demetter P, Boterbert T, Delrue L, Peeters M, Van Damme N (2009) Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: an experimental study with a multitarget tyrosine kinase inhibitor (sunitib), gemcitabine and radiotherapy. Oncol Rep 22:105–113. doi:10.3892/or_00000412 PubMedCrossRefGoogle Scholar
  42. 42.
    Squadriano M, Fazio N (2010) Chemotherapy in pancreatic adenocarcinoma. Eur Rev Med Phamacol Sci 14:386–394Google Scholar
  43. 43.
    Jackson L, Evers BM (2006) Chronic inflammation and pathogenesis of GI and pancreatic cancers. Cancer Treat Res 130:39–65PubMedCrossRefGoogle Scholar
  44. 44.
    Lipton A, Campbell-Baird C, Witters L, Harvey H, Ali S (2010) Phase II trial of gemcitabine, irinotecan, and celecoxib in patients with advanced pancreatic cancer. J Clin Gastroenterol 44:286–288. doi:10.1097/MCG.0b013e3181cda097 PubMedCrossRefGoogle Scholar
  45. 45.
    Brembeck FH, Schoppmeyer K, Leupold U, Gornistu C, Keim V, Mössner J, Riecken E-O, Rosewicz S (1998) A phase II pilot trial of 13-cis retinoic acid and interferon-α in patients with advanced pancreatic carcinoma. Cancer 83:2317–2323PubMedCrossRefGoogle Scholar
  46. 46.
    Michael A, Hill M, Maraveyas A, Dalgleish A, Lofts F (2007) 13-cis-Retinoic acid in combination with gemcitabine in the treatment of locally advanced and metastatic pancreatic cancer–report of a pilot phase II study. Clin Oncol (R Coll Radiol) 19:150–153CrossRefGoogle Scholar
  47. 47.
    Singh B, Murphy RF, Ding X-Z, Roginsky AB, Bell RH Jr, Adrian TE (2007) On the role of transforming growth factor-β in the growth inhibitory effects of retinoic acid in human pancreatic cancer cells. Mol Cancer 6:82. doi:10.1186/1476-4598-6-82 PubMedCrossRefGoogle Scholar
  48. 48.
    Dong Y-W, Wang X-P, Wu K (2009) Suppression of cancer growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition. World J Gastroenterol 15:441–448. doi:10.3748/wjg.15.441 PubMedCrossRefGoogle Scholar
  49. 49.
    Li J, Orr B, White K, Belogortseva N, Niles R, Boskovic G, Dykes A, Park M (2009) Chmp 1A is a mediator of the anti-proliferative effects of all-trans retinoic acid in human pancreatic cancer cells. Mol Cancer 8:7. doi:10.1186/1476-4598-8-7 PubMedCrossRefGoogle Scholar
  50. 50.
    Ruiz-Rabelo JF, Vasquez R, Parea MD, Cruz A, Gonzalez R, Romero A, Munoz-Villanueva MC, Tunez I, Montilla P, Muntane J, Padillo FJ (2007) Beneficial properties of melatonin in an experimental model of pancreatic cancer. J Pineal Res 43:270–275. doi:10.1111/j.1600-079X.2007.00472.x PubMedCrossRefGoogle Scholar
  51. 51.
    Fearon KC, Von Meyenfeldt MF, Moses AG, Van Geenen R, Roy A, Gouma DJ, Giacosa A, Van Gossum A, Bauer J, Barber MD, Aaronson NK, Voss AC, Tisdale MJ (2003) Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 52:1479–1486PubMedCrossRefGoogle Scholar
  52. 52.
    Berkson BM, Rubin DM, Berkson AJ (2009) Revisiting the ALA/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 8:416–422PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Adeline Guais
    • 1
  • GianFranco Baronzio
    • 2
    • 3
  • Edward Sanders
    • 1
  • Frédéric Campion
    • 1
  • Carlo Mainini
    • 4
  • Giammaria Fiorentini
    • 5
  • Francesco Montagnani
    • 5
  • Mahsa Behzadi
    • 6
  • Laurent Schwartz
    • 6
    • 8
  • Mohammad Abolhassani
    • 7
  1. 1.BiorébusParisFrance
  2. 2.Family Medecine Area ASL 01 Legnano (Mi)MilanoItaly
  3. 3.METABLOC Research CenterCentro Medico Kines, Castano Primo, (Mi)MilanoItaly
  4. 4.Centro Medico Kines, Castano Primo, (Mi)MilanoItaly
  5. 5.Oncology UnitS. Giuseppe HospitalEmpoli (Florence)Italy
  6. 6.Laboratoire d’informatiqueEcole PolytechniquePalaiseauFrance
  7. 7.Nosco PharmaceuticalsParisFrance
  8. 8.Service de Radiothérapie, AP-HP Hôpital Pitié-Salpétrièrebd. de l’HôpitalParisFrance

Personalised recommendations