title: LYG-202 inhibits the proliferation of human colorectal carcinoma HCT-116 cells through induction of G1/S cell cycle arrest and apoptosis via p53 and p21(WAF1/Cip1) expression.
abstract: We recently established that LYG-202, a new flavonoid with a piperazine substitution, exerts an anti-tumor effect in vivo and in vitro. In the present study, we demonstrate that LYG-202 induces G1/S phase arrest and apoptosis in human colorectal carcinoma HCT-116 cells. Data showed that the blockade of the cell cycle was associated with increased p21(WAF1/Cip1) and Rb levels and reduced expression of cyclin D1, cyclin E, and CDK4. Moreover, PARP cleavage, activation of caspase-3, caspase-8, and caspase-9, and an increased ratio of Bax/Bcl-2 were detected in LYG-202-induced apoptosis. Additionally, activation of p53 resulted in the up-regulation of its downstream targets PUMA and p21(WAF1/Cip1), as well as the down-regulation of its negative regulator MDM2, suggesting that the p53 pathway may play a crucial role in LYG-202-induced cell cycle arrest and apoptosis. Furthermore, siRNA knockdown of p53 attenuated the G1 cell cycle arrest and apoptosis induced by LYG-202, as the effects of LYG-202 on up-regulation of p21(WAF1/Cip1) and down-regulation of Bcl-2 and pro-caspase-3 were partly inhibited in p53 siRNA transfected cells compared with control siRNA transfected cells. Collectively, these data indicate that LYG-202 exerts its anti-tumor potency by activating the p53-p21 pathway for G1/S cell cycle arrest and apoptosis in colorectal cancer cells.
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Tongjiaxiang, Nanjing, the People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Dai
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Libin
authors.initials: L
authors.lastname: Wei
authors.forename: Jun
authors.initials: J
authors.lastname: Ha
authors.forename: Jingjing
authors.initials: J
authors.lastname: Rong
authors.forename: Rong
authors.initials: R
authors.lastname: Mu
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D047309:Flavones / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D010879:Piperazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047309:Flavones; C541987:LYG 202; D010879:Piperazines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53