title: VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo.
abstract: 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.
authors.affiliation: Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Zheren
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Bao
authors.affiliation: Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Fangzhen
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage* / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; C585120:VS-5584; D058570:TOR Serine-Threonine Kinases