Resistance to apoptosis is correlated with the reduced caspase-3 activation and enhanced expression of antiapoptotic proteins in human cervical multidrug-resistant cells

Recent studies have indicated that induction of apoptosis is the primary cytotoxic mechanism of most cancer chemotherapeutic agents, and abnormalities in the control of apoptosis can affect the sensitivity of malignant cells to multiple drugs. Here, we treated cells with cisplatin and other apoptotic stimuli and found that multidrug-resistant (MDR) endocervical HEN-16-2/CDDP cells, compared with drug-sensitive parental cells, were significantly more resistant to apoptosis and exhibited decreased proteolytic activation of caspase-3. The latter was further demonstrated by decreased cleavage of its substrate poly(ADP-ribose) polymerase (PARP). Further, Western blot analysis showed that MDR HEN-16-2/CDDP cells had significantly higher levels of the apoptosis inhibiting proteins BAG-1 p50 and p33 isoforms and Bcl-X-L. This study provided the first evidence that overexpression of antiapoptotic BAG-1 p50 and p33 and Bcl-X-L may cause resistance to apoptosis through reduction of caspase-3 activity in human cervical cells having an MDR phenotype. (C) 2000 Academic Press.