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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.

It is vital to develop new therapeutic agents for the treatment of melanoma. In the current study, we studied the potential effect of Compound 13 (C13), a novel α1-selective AMP-activated protein kinase (AMPK) activator, in melanoma cells. We showed that C13 exerted mainly cytostatic, but not cytotoxic activities in melanoma cells. C13 potently inhibited proliferation in melanoma cell lines (A375, OCM-1 and B16), but not in B10BR melanocytes. Meanwhile, the AMPK activator inhibited melanoma cell cycle progression by inducing G1-S arrest. Significantly, we failed to detect significant melanoma cell death or apoptosis after the C13 treatment. For the mechanism study, we showed that C13 activated AMPK and inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling in melanoma cells through interaction with the α1 subunit. Short hairpin RNA (shRNA)-mediated knockdown of AMPKα1 not only blocked C13-mediated AMPK activation but also abolished its antiproliferative activity against melanoma cells. Together, these results show that C13 inhibits melanoma cell proliferation through activating AMPK signaling. Our data suggest that C13 along with other small molecular AMPK activators may be beneficial for patients with melanoma.

Background: Major depressive disorder (MDD) is a serious mental disorder that represents a substantial public health problem. Several trials have been undertaken to investigate the role of botulinum toxin type A (BTX-A) in the treatment of MDD, but the conclusions were controversial. To examine the efficacy and safety of BTX-A vs. placebo on patients with a clinical diagnosis of MDD, we conducted this systematic review and meta-analysis.Methods: A systematic search was conducted for all relevant randomized controlled trials (RCTs) in PubMed and Web of Science from inception to June 17, 2020. All published studies that investigated the efficacy and safety of BTX-A injections on patients with a clinical diagnosis of MDD were included. The overall effect size was summarized using a random-effects meta-analysis model. The primary outcomes of the present meta-analysis were the changes in depressive rating scale at week 6 after BTX-A injection compared with placebo. The safety of BTX-A injections also was assessed.Results: Five RCTs with a total of 417 participants (189 patients in the BTX-A group, 228 patients in placebo group) were eligible in this meta-analysis. The results indicated an overall positive effect of BTX-A injections for reducing the depressive symptoms of patients with MDD (Hedges' g, −0.82; 95% CI, −1.38 to −0.27) with large effect size. Differences are likely explained by the dose of BTX-As and the gender of the participants. Our findings also highlighted that BTX-A injections were generally well-tolerated, with only mild and temporary adverse events reported.Conclusions: The present meta-analysis provides evidence that BTX-A injections are associated with a statistically significant improvement in depressive symptoms. BTX-A injections are generally safe and may provide a new, alternative option for the treatment of depression.