A new amide alkaloid induces the apoptosis of human melanoma A375 cells via inhibition of the STAT3 signaling pathway
NEW JOURNAL OF CHEMISTRY(2023)
摘要
Melanoma is the deadliest invasive skin cancer, posing a serious threat to human health. Emerging evidence has shown that STAT3 is a major oncogene in melanoma and validated as a target for melanoma therapy. In this study, we synthesized a new amide alkaloid, (R)-2-(butylamino)-N-(4-((4-methylpiperazine-1-yl) methyl) phenyl)-4-(piperidine-3-ylamino) pyrimidine-5-carboxamide (ZYL-01). AG490 (the antagonist of STAT3) and the human melanoma A375 cells and A375 cells transfected with the STAT3C expression construct (A375-STAT3-3C) or with an empty vector (A375-STAT3-NC) are used to investigate the effects of ZYL-01 treatment of human melanoma A375 cells and determine the relevant mechanisms. Our results showed that ZYL-01 significantly reduced the A375 cell index, inhibited A375 cell proliferation and migration capacity, reduced the levels of MMP and increased the levels of ROS, Ca2+, and apoptosis in A375, A375-STAT3-3C and A375-STAT3-NC cells in a dose-dependent manner. The effect of AG490 was more significant compared to cells without AG490, and the effect of A375-STAT3-NC cells was more significant than A375-STAT3-3C cells. ZYL-01 markedly increased the expression of Bax and cleaved caspase-3 and reduced Bcl-2 and p-STAT3. In conclusion, our results suggest that ZYL-01 could inhibit the activity of A375 cells by inducing cells apoptosis via inhibiting the STAT3 signaling pathway.
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