title: YQ36: a novel bisindolylmaleimide analogue induces KB/VCR cell death.
abstract: Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway.
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Cao
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Xinglu
authors.initials: X
authors.lastname: Zhou
authors.forename: Jianshu
authors.initials: J
authors.lastname: Lou
authors.forename: Difeng
authors.initials: D
authors.lastname: Zhu
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D018432:Drug Resistance, Multiple / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008301:Maleimides / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C550089:3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo(3,4-b)pyridin-3-yl)-1H-pyrrole-2,5-dione; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007211:Indoles; D008301:Maleimides; D011758:Pyrroles; C088060:bisindolylmaleimide