Human breast cancer cells display different sensitivities to ABT-263 based on the level of survivin

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>ABT-263 (navitoclax), a Bcl-2 family protein inhibitor, was clinically tested as an anti-cancer agent. However, the clinical trials were limited given the occurrence of resistance to monotherapy in breast cancer cells. Our study investigates the mechanisms for overcoming navitoclax resistance by combining it with an mTOR inhibitor to indirectly target survivin. The apoptotic effects of navitoclax occurred in MDA-MB-231 breast cancer cells in a time- and dose-dependent fashion, but MCF-7 cells were resistant to navitoclax treatment. The expression of Bcl-2 family genes was not altered by navitoclax, but the expression of survivin, a member of the inhibitors of apoptosis proteins (IAP) family, was downregulated, which increased death signaling in MDA-MB-231 cells. In MCF-7 cells, a navitoclax-resistant cell line, combined treatment with navitoclax and everolimus synergistically reduced survivin expression and induced cell death. These data indicate that navitoclax induces cell death in MDA-MB-231 cells but not in MCF-7 cells. Decreased survivin expression in MDA-MB-231 cells may be a primary pathway for death signaling. Combined navitoclax and everolimus treatment induces cell death by reducing the stability of survivin in MCF-7 cells. Given that survivin-targeted therapy overcomes resistance to navitoclax, this strategy could be used to treat breast cancer patients.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MDA-MB-231 and MCF-7 cell lines exhibit differential sensitivity to navitoclax induced apoptosis. </LI> <LI> Navitoclax-induced apoptotic cell death occurs through the regulation of survivin. </LI> <LI> Reduced expression levels of survivin restore navitoclax sensitivity in MCF-7 cell lines. </LI> <LI> Combined treatments with navitoclax and everolimus induces cell death in MCF-7 cells. </LI> </UL> </P>