Actinomycin V Induces Apoptosis Associated with Mitochondrial and PI3K/AKT Pathways in Human CRC Cells |
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| Authors: | Shiqing Jiang E Zhang Hang Ruan Jiahui Ma Xingming Zhao Yaoyao Zhu Xiaoyu Xie Ningning Han Jianjiang Li Hao Zhang Weidong Xie Xia Li |
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| Institution: | 1.Department of Marine Sciences, Marine College, Shandong University, Weihai 264209, China; (S.J.); (E.Z.); (H.R.); (J.M.); (X.Z.); (Y.Z.); (X.X.); (N.H.); (J.L.); (H.Z.); (W.X.);2.Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China |
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| Abstract: | Actinomycin (Act) V, an analogue of Act D, presented stronger antitumor activity and less hepatorenal toxicity than Act D in our previous studies, which is worthy of further investigation. We hereby report that Act V induces apoptosis via mitochondrial and PI3K/AKT pathways in colorectal cancer (CRC) cells. Act V-induced apoptosis was characterized by mitochondrial dysfunction, with loss of mitochondria membrane potential (MMP) and cytochrome c release, which then activated cleaved caspase-9, cleaved caspase-3, and cleaved PARP, revealing that it was related to the mitochondrial pathway, and the apoptotic trendency can be reversed by caspase inhibitor Z-VAD-FMK. Furthermore, we proved that Act V significantly inhibited PI3K/AKT signalling in HCT-116 cells using cell experiments in vitro, and it also presented a potential targeted PI3Kα inhibition using computer docking models. Further elucidation revealed that it exhibited a 28-fold greater potency than the PI3K inhibitor LY294002 on PI3K inhibition efficacy. Taken together, Act V, as a superior potential replacement of Act D, is a potential candidate for inhibiting the PI3K/AKT pathway and is worthy of more pre-clinical studies in the therapy of CRC. |
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| Keywords: | Act V CRC PI3K/AKT apoptosis mitochondrial |
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