Attenuation by glutathione of hsp72 gene expression induced by cadmium in cisplatin-resistant human ovarian cancer cells

Intracellular GSH has some effects on protecting cells against cadmium and is involved in the development of resistance to cisplatin (CDDP). To determine the effects of intracellular GSH on expression of the heat shock genes (hsp) induced by cadmium in CDDP-resistant cancer cells, we used two human ovarian cancer cell lines: CDDP-sensitive A2780 and its CDDP-resistant derivative A2780CP. The concentration of intracellular GSH was significantly higher in A2780CP than in A2780 cells. A2780CP cells were more resistant to CdCl2 exposure than A2780 cells. The treatment of the two cell lines with 50 mu M CdCl2 induced hsp72, hsp32 and metallothionein (MT-II) mRNAs, and the induction level of each mRNA did not differ in the two cell lines. However, the treatment with 20 mu M CdCl2 induced the hsp72 and hsp32 mRNAs in A2780CP cells less than in A2780 cells, while the MT-II mRNA was induced to similar levels in the two cell lines. The DNA binding activity of the heat shock factor (HSF) in response re, 20 mu M CdCl2 exposure was also significantly lower in A2780CP cells. The treatment of A2780 cells with N-acetyl-L-cysteine increased the intracellular GSH concentration, and profoundly suppressed hsp72 mRNA induction and HSF activation by CdCl2. These results indicate that the regulation of the hsp72 gene expression induced by CdCl2 was more suppressive in A2780CP than in A2780 cells. Our findings suggest that increased GSH biosynthesis in CDDP resistant cancer cells may be involved in the attenuation of HSF activation by CdCl2. BIOCHEM PHARMACOL 58;1:69-76, 1999. (C) 1999 Elsevier Science Inc.