Effect of anti-estrogen combined with roscovitine, a selective CDK inhibitor on human breast cancer cells differing in expression of ER
Nora Zulehner, Margarita Maurer and Józefa Wesierska-Gadek
Roscovitine (ROSC), a selective inhibitor of cyclindependent kinases (CDKs) reduces numbers of cancer cells in a concentration-dependent manner. At low doses ROSC arrests cell cycle progression and at higher doses it induces apoptosis. ROSC efficiently inhibits proliferation of human ER-α positive MCF-7 breast cancer cells by inducing G2/M arrest and concomitantly initiates apoptosis by a p53-dependent pathway. However, the effect of ROSC is much weaker on MCF-7 cells maintained in the presence of estrogen-mimicking compounds. Therefore, we have examined the action of ROSC on other breast cancer cell lines differing in ER status and confirmed that tamoxifen (TAM) affects the efficacy of this CDK inhibitor. ROSC was effective against all tested breast cancer cell lines, arresting them at G1/S or G2/M transition and inducing apoptosis in SKBR-3 cells. Interestingly, TAM affected all tested cell lines, irrespective of their ER-α status, and in combination with ROSC it enhanced G1 or G2 arrest. Our results provide evidence that ROSC can be combined with antiestrogen therapy and that the mode of ROSC action strongly depends on the cellular context. The effect of TAM on ER-negative cancer cells indicates that TAM also crosstalks with other steroid hormone receptors.
Keywords: Tamoxifen, MCF-7, BT-20, SKBR-3, G2 arrest, cell cycle arrest, selective estrogen receptor modulators, SERM, p53 tumor suppressor