Abstract
The purpose of the study was to examine the role of caspases in signaling pathways of apoptosis induced by free doxorubicin (DOX) and HPMA copolymer-bound DOX (P(GFLG)–DOX) in human ovarian carcinoma cells. Sensitive A2780 and DOX resistant A2780/AD cells were exposed to different doses of drugs within 12, 18, 24 and 36 h. Caspase activity, expression of genes encoding human caspases 1–10, Apaf-1 and bcl-2 proteins and apoptosis were studied. In sensitive cells both free and P(GFLG)–DOX activated caspases 3, 7 and 9. In addition, P(GFLG)–DOX activated caspases 6 and 8. In resistant cells apoptosis induced by free DOX depended on the activation of caspases 2, 7 and 9, while caspase 3 was not involved; this explains the low degree of apoptosis induced by free DOX in resistant cells. P(GFLG)–DOX triggered the additional caspases 3, 6 and 8. A more pronounced degree of caspase activation and apoptosis after the action of P(GFLG)–DOX depended on the inhibition of bcl-2-encoded cellular defensive mechanisms and a more significant activation of Apaf-1. It was concluded that HPMA copolymer-bound DOX induced additional caspase-dependent apoptosis signaling pathways and the degree of the induction was higher, which led to more pronounced apoptosis when compared to free DOX.
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