Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

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Abstract
Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway; it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.
Funding Information
  • National Natural Science Foundation of China (81573589, 81773890, 81603281)
  • Science & Technology Department of Sichuan Province (2017JQ0002, 2017TD0001, 2016TD0006)

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