State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
Int J Mol Sci. 2020 Mar 7;21(5):1845. doi: 10.3390/ijms21051845.
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.
黑色素瘤是皮肤癌中最致命的一种，在过去的 20 年中，其发病率持续上升。因此，迫切需要发现一种新的针对黑色素瘤的靶向治疗策略。在我们的研究中，通过 MTT 基于细胞增殖测定法、流式细胞术的细胞周期和凋亡测定法、蛋白质免疫印迹、蛋白质免疫沉淀、设计黑色素瘤异种移植模型以及免疫组织化学/免疫荧光测定法，确定了一种新型 HSP90-PI3K 双重抑制剂的详细分子机制。我们的化合物命名为 DHP1808，通过激活 Fas/FasL 信号通路诱导细胞凋亡来抑制 A375 细胞的增殖；它还通过干扰 Hsp90-EGFR 相互作用和下游信号通路来诱导细胞周期停滞并抑制 A375 细胞的迁移和侵袭。我们的结果表明，DHP1808 可能是一种有前途的 HSP90/PI3K 双重抑制剂的先导化合物。
