BCL-2 and GST-π overexpression in H69/CDDP and enhanced superoxide dismutase activity in PC9/CDDP and PC14/CDDP may play roles in their cisplatin resistance

To investigate the mechanism of cisplatin (CDDP) resistance in the CDDP resistant sublines H69/CDDP, PC9/CDDP, and PC14/CDDP, we examined the levels of glutathione S-transferases (GSTs), Bcl-2, catalase, superoxide dismutase (SOD) activity, and CDDP mediated DNA fragmentation. H69/CDDP overexpressed GST-π polypeptides at approximately 10 times higher level than the parent line with no induction of GST-L isoform and catalase. PC9 and PC14 cell lines retained high basal level of GST-π similar to that of H69/CDDP and did not further induce GST π during the development of CDDP resistance. Basal SOD activity was higher in the NCI H69 cell line, but lower in PC9 and PC14 cell lines. However during the acquirement of CDDP resistance in PC9/CDDP and PC14/ CDDP cells, marked induction of SOD activity was observed in comparison to the marginal increase of SOD level in H69/CDDP cells. In addition to the cellular modification in the molecules implicated in the CDDP bioinactivation, Bcl-2 was markedly overexpressed in H69/CDDP and slightly enhanced in PC14/CDDP, but not in PC9/CDDP. By fluorescence observation of the apoptotic DNA fragmentation, it was shown that CDDP mediated apoptosis was delayed in H69/CDDP more than in the parent line. Therefore, molecular modifications during the development of CDDP resistance such as overexpression of Bcl-2 and GST-π polypeptides in H69/CDDP and enhanced SOD activity in PC9/CDDP and PC14/CDDP may play important roles in CDDP resistance.