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

• Published in: International journal of oncology Vol. 45; no. 2; pp. 804 - 812
• Main Authors: XIE, GUI'E, TANG, HONGPING, WU, SHAOQING, CHEN, JINGSONG, LIU, JIANGWEN, LIAO, CAN
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.08.2014; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Blotting, Western; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Clinical trials; Cyclin-Dependent Kinase 2; cyclin-dependent kinases; Cytotoxicity; Development and progression; Dose-response relationship (Biochemistry); Female; Genetic aspects; Health aspects; Heterografts; Humans; In Situ Nick-End Labeling; Kinases; Mcl-1; Mice; Mice, Inbred BALB C; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Observations; Oxazoles - pharmacology; Phosphotransferases; Proteins; Real-Time Polymerase Chain Reaction; Rodents; SNS-032; Thiazoles - pharmacology; Tumors; X-Linked Inhibitor of Apoptosis Protein; United States > US
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2014.2467

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.