Enhanced Antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro
Menée à l'aide d'un modèle murin et de lignées cellulaires de cancer humain du poumon non à petites cellules, cette étude évalue l'efficacité conjointe du 3-bromopyruvate et de la rapamycine, administrés sous forme d'aérosol, pour prévenir la survenue de la maladie, puis identifie le mécanisme d'action associé
3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the Serine/Threonine protein kinase "mammalian target of rapamycin (mTOR). Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-Bromopyruvate and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3- bromopyruvate did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-bromopyruvate, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.
Cancer Prevention Research , résumé, 2015