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Down‐regulation of apoptosis‐related bcl‐2 but not bcl‐xL or bax proteins in multidrug‐resistant MCF‐7/Adr human breast cancer cells

Recent studies have shown that high levels of the apoptosis‐related proteins bcl‐2 and bcl‐xL increase, while over‐expression of bcl‐xS or bax decreases, resistance to drugs that induce apoptosis in some human cancer cells. In the present report, we investigated whether expression of these apoptosis‐related proteins correlates with changes in the degree of resistance to apoptosis induced by doxorubucin, taxol, vincristine and VP‐16 and contributes to the development of acquired resistance in multidrug‐resistant MCF‐7/Adr breast cancer cells. In this study, high levels of bcl‐xL and bax proteins are detected in both MCF‐7 and MCF‐7/Adr cells. In contrast, bcl‐2 protein is down‐regulated about 10‐fold in MCF‐7/Adr cells compared with MCF‐7 cells. RT‐PCR analysis showed that MCF‐7/Adr cells express approximately 2‐fold less bcl‐2 mRNA than MCF‐7 cells. Moreover, 4–24 hr cycloheximide treatment of MCF‐7 and MCF‐7/Adr cells did not affect the expression of bcl‐2 protein, indicating that this protein is very stable in both cell lines. Our results suggest that bcl‐2 expression is modulated partly by transcriptional, but mainly by post‐transcriptional, mechanisms. Despite the down‐regulation of bcl‐2 in MCF‐7/Adr cells and equal levels of bcl‐xL and bax proteins in both cell lines, cytoplasmic DNA‐histone complexes induced by doxorubucin, taxol, vincristine and VP‐16 indicate that MCF‐7/Adr cells are highly resistant to apoptosis. Moreover, treatments of MCF‐7/Adr cells with P‐glycoprotein (P‐gp) modulators, cyclosporin A and verapamil increased doxorubicin and vincristine‐induced DNA fragmentation about 1.4‐ and 2.5‐fold, indicating that P‐gp is involved in the development of resistance to chemotherapy‐induced apoptosis in this cell line. © 1996 Wiley‐Liss, Inc.