Relationships between proto-oncogene expression and apoptosis induced by anticancer drugs in human prostate tumor cells

Abstract

A variant of human prostate PC3 cells, isolated from PC3 cells, was shown to be significantly resistant (>x 10-fold) to several clinically active anticancer drugs, including VP-16 and cisplatin. Previous studies showed that resistance to these drugs was not due to expression of the mdr1 gene, or modifications in topoisomerases but may have resulted from high expressions of certain proto-oncogenes (Yamazaki et al. (1994) Biochim. Biophys. Acta 1226, 89–96). Flow cytometry, DNA gel electrophoresis and northern blot analysis were used to further characterize drug responses in sensitive and resistant cells. Treatment of the sensitive PC3 cells with VP-16 and CDDP resulted in accumulation of cells in S and G2, and G1 and S phases, respectively, and caused significant degradation of the genomic DNA into intemucleosomal sized DNA fragments, indicating apoptosis. In contrast, resistant PC3 cells showed little or no DNA fragmentation. Resistant POW cells expressed 2–3-fold more bc12 protein than the parental PC3 cells, and overexpressed c- myc, c - jun and H- ras mRNA compared to sensitive cells. Treatment with VP-16 or CDDP significantly induced c- myc mRNA levels in sensitive PC3 cells. H- ras message was not affected by either VP-16 or CDDP treatment in PC3 cells. These studies, taken together, suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to altered levels of bc12 and/or oncogene overexpression in PC3(R) cells.