title: LYG-202 exerts antitumor effect on PI3K/Akt signaling pathway in human breast cancer cells.
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.
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Yin
authors.forename: Youxiang
authors.initials: Y
authors.lastname: Ding
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.forename: Na
authors.initials: N
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047309:Flavones; C541987:LYG 202; D010879:Piperazines; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt