Aim: ZCJ14, a gefitinib analog, exhibited prominent anti-cancer effect both in vitro and in vivo. The present study aims to investigate the inhibitory effects of ZCJ14 on human cancer cells, and explored its possible mechanism of action.
Main methods: The inhibitory effect of ZCJ14 on human-derived tumor cells in vitro was mainly measured by MTT and colony formation assays. The nude mouse xenograft models were established to figure out the inhibitory effect of ZCJ14 on solid tumors in vivo. Western blotting assays were used to detect the phosphorylation level of EGFR down-streaming proteins and the proteomic technique was used to study the proteome alterations of cancer cells triggered by ZCJ14.
Key findings: ZCJ14 inhibited the proliferation of A549 (lung cancer), HCT116 (colorectal cancer) and MCF-7 (breast cancer) cells in vitro with 48 h IC50 values of 0.83, 0.85 and 0.92 μM, respectively. It suppressed the growth of A549, NCI-H1975, NCI-H1299 and MCF-7, HCT116 tumors in mouse xenograft models, and had almost no toxicity. At the same dose, the inhibitory effect of ZCJ14 on solid tumors was better than the corresponding positive drugs. ZCJ14 does not exert anti-tumor effects through inhibition of EGFR pathway, but by enhancing steroid biosynthesis and inhibiting ubiquitin-mediated proteolysis.
Significance: Based on the excellent anti-tumor effect of ZCJ14 on human tumor cell lines, it can be used as an effective anti-tumor drug candidate. In addition, the results of proteomic study in this paper can provide clues for further study of the anti-tumor mechanism of ZCJ14.
Keywords: Novel anti-tumor agent; Proteomics; Steroid metabolism; Ubiquitin-mediated proteolysis; ZCJ14.
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