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

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

  • Apoptosis. 2015 Sep;20(9):1253-69. doi: 10.1007/s10495-015-1145-x.
Yue Zhao 1 Xiaoping Wang Yang Sun Yuxin Zhou Yuehan Yin Youxiang Ding Zhiyu Li Qinglong Guo Na Lu
Affiliations

Affiliation

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
Abstract

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.

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  • HY-115436
    98.01%, 抗血管生成/抗肿瘤剂