VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo

• Published in: PloS one 2015-07, Vol.10 (7), p.e0132655-e0132655
• Main Authors: Shao, Zheren, Bao, Qi, Jiang, Fangzhen, Qian, Huan, Fang, Quan, Hu, Xueqing
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adjuvants; AKT protein; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Bcl-2 protein; Bcl-x protein; Biocompatibility; Caspase inhibitors; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclin D1; Cytotoxicity; Gene Expression Regulation, Neoplastic - drug effects; Growth; Humans; Inhibitors; Keratinocytes; Kinases; Male; Medical schools; Melanocytes; Melanoma; Melanoma - drug therapy; Melanoma - enzymology; Mice; Morpholines - administration & dosage; Morpholines - pharmacology; Oral administration; Penicillin; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Plastic surgery; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Purines - administration & dosage; Purines - pharmacology; Rapamycin; Signal transduction; Signaling; siRNA; Skin; Skin cancer; Skin diseases; Skin Neoplasms - drug therapy; Skin Neoplasms - enzymology; Studies; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; Toxicity; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0132655

Melanomas cause over 76% of skin cancer deaths annually. Phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is important for melanoma initiation and progression. In the current study, we evaluated the potential anti-melanoma effect of VS-5584, a novel and highly potent PI3K-mTOR dual inhibitor. We demonstrated that VS-5584 potently inhibited survival and proliferation of established (A375, A-2058 and SK-MEL-3 lines) and primary human melanoma cells, but was non-cytotoxic to non-cancerous human skin keratinocytes and B10BR murine melanocytes. At the meantime, VS-5584 induced caspase-dependent apoptotic death in melanoma cells, and its cytotoxicity was alleviated by the caspase inhibitors. At the molecular level, VS-5584 blocked AKT-mTOR activation and downregulated cyclin D1 expression in melanoma cells, while the expressions of Bcl-xL and Bcl-2 were not affected by VS-5584 treatment. On the other hand, a BH-3 mimetic Bcl-xL/Bcl-2 inhibitor ABT-737, as well as siRNA-mediated knockdown of Bcl-xL or Bcl-2, enhanced the activity of VS-5584 in melanoma cells. In vivo, oral administration of VS-5584 suppressed A375 melanoma xenograft growth in nude mice, and its activity was further enhanced by co-administration of ABT-737. These results provide the rationale for the clinical assessment of VS-5584 in melanoma patients and development of ABT-737 and other Bcl-xL/Bcl-2 inhibitors as the possible adjuvants.