LYG-202 exerts antitumor effect on PI3K/Akt signaling pathway in human breast cancer cells.

In this study, we aimed to investigate the antitumor effect of LYG-202, a newly synthesized piperazine-substituted derivative of flavonoid on human breast cancer cells and illustrate the potential mechanisms. LYG-202 induced apoptosis in MCF-7, MDA-MB-231 and MDA-MB-435 cells. LYG-202 triggered the activation of mitochondrial apoptotic pathway through multiple steps: increasing Bax/Bcl-2 ratio, decreasing mitochondrial membrane potential (ΔΨ(m)), activating caspase-9 and caspase-3, inducing cleavage of poly(ADP-ribose) polymerase, cytochrome c release and apoptosis-inducing factor translocation. Furthermore, LYG-202 inhibited cell cycle progression at the G1/S transition via targeting Cyclin D, CDK4 and p21(Waf1/Cip1). Additionally, LYG-202 increased the generation of intracellular ROS. N-Acetyl cysteine, an antioxidant, reversed LYG-202-induced apoptosis suggesting that LYG-202 induces apoptosis by accelerating ROS generation. Further, we found that LYG-202 deactivated the PI3K/Akt pathway, activated Bad phosphorylation, increased Cyclin D and Bcl-xL expression, and inhibited NF-κB nuclear translocation. Activation of PI3K/Akt pathway by IGF-1 attenuated LYG-202-induced apoptosis and cell cycle arrest. Our in vivo study showed that LYG-202 exhibited a potential antitumor effect in nude mice inoculated with MCF-7 tumor through similar mechanisms identified in cultured cells. In summary, our results demonstrated that LYG-202 induced apoptosis and cell cycle arrest via targeting PI3K/Akt pathway, indicating that LYG-202 is a potential anticancer agent for breast cancer.
AuthorsYue Zhao, Xiaoping Wang, Yang Sun, Yuxin Zhou, Yuehan Yin, Youxiang Ding, Zhiyu Li, Qinglong Guo, Na Lu
JournalApoptosis : an international journal on programmed cell death (Apoptosis) Vol. 20 Issue 9 Pg. 1253-69 (Sep 2015) ISSN: 1573-675X [Electronic] Netherlands
PMID26153346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

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