Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression |
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Authors: | Doisneau-Sixou Sophie F Cestac Philippe Faye Jean-Charles Favre Gilles Sutherland Robert L |
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Institution: | Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia. |
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Abstract: | The efficacy of tamoxifen in the hormonal therapy of breast cancer is well established, but therapeutic resistance is inevitable. FTIs are a new class of anticancer drugs that are in phase III clinical evaluation. Since the mechanisms of action of these 2 classes of drugs are different, we tested the combination of tamoxifen and FTI-277 on inhibiting proliferation of hormone-dependent MCF-7 human breast cancer cells. An additive effect on cell proliferation was demonstrated, accompanied by an additive G(0)/G(1) arrest. The major effect of the combination of the 2 drugs was to maintain p21(waf/cip1) at an intermediate level, higher than that observed in the presence of tamoxifen alone. This was associated with an additive effect on inactivation of cyclin E-Cdk2 complexes and decreased phosphorylation of pRb and p130 pocket proteins. These effects were accompanied by increased association of 2 CDIs, p27(kip1) and p21(waf/cip1), with cyclin E-Cdk2 complexes. These data demonstrate that the additive effect is likely predominantly due to the recruitment of p27(kip1) and, to a lesser extent, p21(waf/cip1) into the cyclin E-Cdk2 complexes. Together, these results suggest that the combination of FTI and tamoxifen may increase the antitumor effect of either drug alone in breast cancer. |
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Keywords: | prenylation pocket protein cyclin E p27kip1 p21waf/cip1 |
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