title: The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo.
abstract: Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in many types of cancer cells by inhibiting Cdk7 and Cdk9, which control transcription. SNS-032 is a potent and selective inhibitor of Cdk2, Cdk7 and Cdk9 and has emerged in clinical trials. Here, we examined the viability of MCF-7 and MDA-MB-435 breast cancer cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways in breast cancer cells as shown by a dose-dependent increase in Annexin V-positive cells and terminal deoxynucleotidyl transferase-mediated dUTP nick?end labeling (TUNEL)-positive cells, as well as activation of caspase-8, -9 and poly(ADP-ribose) polymerase (PARP). At the molecular level, SNS-032 induced a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and blocked RNA synthesis. Consistent with the inherently rapid turnover rates of their transcripts and proteins, the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP) were rapidly reduced on exposure to SNS-032. Our results also indicated that SNS-032 suppressed the growth of breast cancer xenografts in mice. These data demonstrate that the use of SNS-032 may be a rational and novel therapeutic strategy for human breast cancer and warrants further clinical investigation.
authors.affiliation: Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China.
authors.forename: Gui'e
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Pathology, Shenzhen Maternity and Child Healthcare Hospital Affiliated to Southern Medical University, Shenzhen 518028, P.R. China.
authors.forename: Hongping
authors.initials: H
authors.lastname: Tang
authors.affiliation: Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Wu
authors.affiliation: Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Chen
authors.affiliation: College of Light Industry and Food Science, South China University of Technology, Guangzhou 510640, P.R. China.
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, P.R. China.
authors.forename: Can
authors.initials: C
authors.lastname: Liao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D005260:Female; D064593:Heterografts; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010080:Oxazoles / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D013844:Thiazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051357:Cyclin-Dependent Kinase 2