Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice.
- 536 Downloads
Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of α-lipoic acid and hydroxycitrate (METABLOCTM). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial.
KeywordsLipoic acid Hydroxycitrate Octreotide Metabolic enzymes Screening
We acknowledge the help of Jean-Marc Steyaert. The mice studies were performed by Nosco Pharmaceuticals (France) and EPO GmbH (Germany). This work was funded by Biorébus. METABLOC is a trade mark of Biorébus. AG is an employee of Biorébus. The other authors declare that they have no competing interests.
- 13.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
- 16.Israël M, Schwartz L (2005) Cancer as a Dysmethylation Syndrome. John Libbey, ParisGoogle Scholar
- 17.Israël M, Schwartz L (2011) Carcinogenic mechanisms: anticancer drugs that target tumor metabolism. Biomedical Research 22(2):130–164Google Scholar
- 21.Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (2005) Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, Pharmacology and Toxicology, July 2005.Google Scholar
- 22.Guais A, Baronzio GF, Sanders E, Campion F, Mainini C, Fiorentini G, Montagnani F, Behzadi M, Schwartz L, Abolhassani M (2010) Adding a combination of hydroxycitrate and lipoic acid (METABLOC™) to chemotherapy improves effectiveness against tumor development: experimental results and case report. Investig New Drugs In press 2010 Oct 8. [Epub ahead of print]. doi: 10.1007/s10637-010-9552-x
- 27.Friedlander TW Weinberg VK Small EJ Sharib J Harzstark AL Lin AM Fong L Ryan CJ (2010) Effect of the somatostatin analog octreotide acetate on circulating insulin-like growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: results of a phase II study. Urol Oncol In Press Sep 28. [Epub ahead of print]. doi: 10.1016/j.urolonc.2010.06.014
- 29.Cerovac V, Monteserin-Garcia J, Rubinfeld H, Buchfelder M, Losa M, Florio T, Paez-Pereda M, Stalla GK, Theodroropoulou M (2010) The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells. Cancer Res 70:666–74. doi: 10.1158/0008-5472.CAN-09-2951 CrossRefPubMedGoogle Scholar
- 30.Sun Q, Chen X, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen L, Zhang Y, Goto J, Onda H, Chen T, Wang MR, Lu Y, You H, Kwiatkowski D, Zhang H (2011) Mammalian target of rapamycin up-regulation of pyruvate kinase isoeznzyme type M2 is critical for aerobic glycolysis and tumor growth. PNAS 108:4129–34. doi: 10.1073/pnas.1014769108 CrossRefPubMedGoogle Scholar
- 32.Pouessel D, Culine S, Guillot A, Di Stabile L, Thibaudeau E, Reymond D, Mottet N (2008) Phase II study of TLN-232, a novel M2PK targeting agent administered by CIV to patients with advanced renal cell carcinoma. 33 rd ESMO Congress 12–16 SeptemberGoogle Scholar
- 36.Nayak TK, Atcher RW, Prossnitz ER, Norenberg JP (2008) Enhancement of somatostatin-receptor-targeted (177)Lu-[DOTA(0)-Tyr]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation. Nucl Med Biol 35:673–8. doi: 10.1016/j.nucmedbio.2008.05.003 CrossRefPubMedGoogle Scholar
- 40.Hillman N, Herranz L, Alvarez C, Martínez Olmos MA, Márco A, Gómez-Pan A (1998) Efficacy of octreotide in the regression of a metastatic carcinoid tumour despite negative imaging with In-111-pentetreotide (Octreoscan). Exp Clin Endocrinol Diabetes 106:226–30. doi: 10.1055/s-0029-1211980 CrossRefPubMedGoogle Scholar
- 41.Jia WD, Xu GL, Wang W, Wang ZH, Li JS, Ma JL, Ren WH, Ge YS, Yu JH, Liu WB (2009) A somatostatin analogue, octreotide, inhibits the occurrence of second primary tumors and lung metastasis after resection of hepatocellular carcinoma in mice. Tohoku J Exp Med 218:155–60. doi: 10.1620/tjem.218.155 CrossRefPubMedGoogle Scholar
- 42.Ruessmann HJ (2009) German Society of outpatient diabetes centers AND (Arbeitsgemeinschaft niedergelassener diabetologisch tätiger Arzte e.V.): Switching from pathogenetic treatment with alpha-lipoic acid to gabapentin and other analgesics in painful diabetic neuropathy: a real-world study in outpatients. J Diabetes Complications 23:174–7CrossRefPubMedGoogle Scholar
- 43.Moungjaroen J, Nimmannit U, Callery PS, Wang L, Azad N, Lipipun V, Chanvorachote P, Rojanasakul Y (2006) Reactive oxygen species mediate caspace activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down regulation. J Pharmacol Exp Therapeut 319:1062–9. doi: 10.1124/jpet.106.110965 CrossRefGoogle Scholar
- 44.Mantovani G, Macciò A, Madeddu C, Gramignano G, Serpe R, Massa E, Dessì M, Tanca FM, Sanna E, Deiana L, Panzone F, Contu P et al (2008) Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results. Nutrition 24:305–13. doi: 10.1016/j.nut.2007.12.010 CrossRefPubMedGoogle Scholar