Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumor development: experimental results and case report
- 640 Downloads
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.
KeywordsMetabolic therapy Pyruvate dehydrogenase ATP citrate lyase
We acknowledge the help of Jean-Marc Steyaert. This work was funded by Biorébus.
Written consent for publication was obtained from the patient.
METABLOC is a trade mark of Biorébus.
AG is an employee of Biorébus. The other authors declare that they have no competing interests.
- 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
- 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
- 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
- 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
- 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
- 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
- 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.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.Squadriano M, Fazio N (2010) Chemotherapy in pancreatic adenocarcinoma. Eur Rev Med Phamacol Sci 14:386–394Google Scholar
- 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.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