BCL-2 family protein expression and platinum drug resistance in ovarian carcinoma.
The expression of the BCL-2 family proteins, BCL-2, BAX, BCL(XL) and BAK have been determined in a panel of 12 human ovarian carcinoma cell lines encompassing a wide range in sensitivity to cisplatin. Whereas BAX, BCL(XL) and BAK levels did not correlate with sensitivity, there was a statistically significant inverse correlation (r = -0.81; P = 0.002) between growth inhibition by cisplatin and BCL-2 levels. In sublines possessing acquired resistance to various platinum-based drugs or across a panel of human ovarian carcinoma xenografts, there was no consistent pattern of BCL-2 expression. Two relatively sensitive lines (A2780 and CH1) have been stably transfected with bcl-2 and bcl(XL) respectively and two relatively resistant lines (A2780cisR and SKOV-3) stably transfected with bax. Overexpression of BCL-2 in A2780 cells led to resistance to cisplatin compared to the vector control when assayed at 48 h post-drug incubation but a significant increase in sensitivity at 96 h. Relative rates of apoptosis at 48- and 96-h post-cisplatin exposure mirrored the growth inhibition. There was no significant difference in sensitivity of the pair of lines by clonogenic assay. No significant changes in chemosensitivity to a variety of DNA-damaging or tubulin-interactive agents were observed in the remaining transfected lines. Taken together, these results suggest that, in human ovarian carcinoma cells, high BCL-2 levels (either naturally occurring or through gene transfection) confers a trend towards sensitivity not resistance to platinum drugs.
Beale
P J
PJ
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Sutton, UK.
Rogers
P
P
Boxall
F
F
Sharp
S Y
SY
Kelland
L R
LR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002945:Cisplatin