M 4 IDP, a zoledronic acid derivative, induces G1 arrest, apoptosis and autophagy in HCT116 colon carcinoma cells via blocking PI3K/Akt/mTOR pathway

摘要

Abstract Aims The aim of this work was to examine the antitumor effects and mechanisms of M 4 IDP, a zoledronic acid derivative, on human colorectal cancer (CRC) HCT116 cells. Main methods The effects of M 4 IDP on proliferation, cell cycle and ROS production were determined by CCK-8 and flow cytometry assays. Annexin-V-FITC/PI, Hoechst 33258, MDC staining assays and Ad-mCherry-GFP-LC3B fluorescence assay were performed to investigate apoptosis and autophagy. The effects of M 4 IDP on the induction of ER stress as well as the expression of cell cycle, apoptosis and autophagy-related proteins were analyzed by western blot assay. Key findings M 4 IDP exhibited strong and sustained inhibitory effect on the growth of HCT116 cells. G1 arrest caused by M 4 IDP might be attributed to the enhancement of p27 and reduction of cyclin D1 expression. Proper-time treatment of M 4 IDP activated autophagy and promoted autophagic flux, while long-time treatment might inhibit the autophagic degradation and undermine the autophagy. M 4 IDP-induced apoptosis and autophagy were related to the ROS production and subsequent ER stress. M 4 IDP treatment increased the expression of PTEN, inhibited the phosphorylation of PDK1, Akt, mTOR, p70S6K, and increased the phosphorylation of GSK-3β and Bad, suggesting that the inhibition of PI3K/Akt/mTOR pathway might be involved in the antitumor activities of M 4 IDP. Significance Our study indicates the antitumor properties of M 4 IDP and its potential clinical use in CRC therapy by blocking PI3K/Akt/mTOR pathway. This study also provides a better understanding of the antitumor effects and the underlying mechanisms of bisphosphonates in the field of CRC therapy. ]]>