Abstract 3490: Selective estrogen receptor modulators enhance efficacy of small molecule CDK inhibitors on human breast cancer cells differing in the expression of ER

Abstract

Abstract Inactivation of cyclin-dependent kinases (CDKs) by pharmacological inhibitors is a very effective weapon against malignant cells. Roscovitine (ROSC), a selective CDK inhibitor primarily affecting CDK2, CDK1, and CDK7, reduces the number of human cancer cells in a concentration-dependent manner. At lower doses ROSC arrests cell cycle progression and at higher doses it induces apoptosis. ROSC inhibits efficiently proliferation of human ER+-ve MCF-7 breast cancer cells by induction of cell cycle arrest at the G2/M transition [1] and concomitantly initiates apoptosis by a p53-dependent pathway [2]. However, the effect of ROSC was much weaker in MCF-7 cells maintained in the presence of estrogen-mimicking compounds [3]. Therefore, we decided to examine the action of selective CDK inhibitors on other breast cancer cell lines differing in the status of p53 and ER and to prove the impact of selective estrogen receptor modulators (SERMs) on the efficacy of ROSC and olomoucine II (OLO II), a new pharmacological CDK inhibitor. ROSC and OLO II were effective on all tested breast cancer cell lines. They arrested MCF-7 and BT-20 cells at G2/M transition and SKBR3 cells in G1 phase and additionally induced apoptosis. The effect of the inhibition of CDKs on distinct cell cycle regulators and pro-survival factors was studied. Interestingly, SERM strongly affected all tested cell lines irrespective of their ER status. Its combination with CDK inhibitors had a different impact. It enhanced G1 or G2 arrest. Our results provide evidence that both CDK inhibitors exert a strong anti-proliferative and pro-apoptotic effect and that their mode of action depends on the cellular context. Moreover, our findings demonstrate that pharmacological CDK inhibitors can be combined with anti-estrogen therapy. The strong effect of anti-estrogens on ER-negative cancer cells indicates that SERMs crosstalk with other steroid hormone receptors. [1] Wojciechowski J. et al. 2003. Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine-induced apoptosis of human MCF-7 breast cancer cells. Int J Cancer 106: 486-95. [2] Wesierska-Gadek J. et al. 2005. Roscovitine-induced up-regulation of p53AIP1 protein precedes the onset of apoptosis in human breast cancer cells. Mol Cancer Ther 4: 113-124. [3] Wesierska-Gadek J. et al. 2006. Phenol red reduces ROSC mediated cell cycle arrest and apoptosis in human MCF-7 cells. J Cell Biochem. 98: 1369-1379. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3490.