title: Preliminary evaluation of caspases-dependent apoptosis signaling pathways of free and HPMA copolymer-bound doxorubicin in human ovarian carcinoma cells.
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.
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Rm. 301, Salt Lake City, UT 84112, USA.
authors: T
authors: T
authors: Minko
authors: P
authors: P
authors: Kopecková
authors: J
authors: J
authors: Kopecek
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D005079:Excipients; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019940:Genes, bcl-1 / Q000187:drug effects; D006801:Humans; D008689:Methacrylates / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: C506592:APAF1 protein, human; D000903:Antibiotics, Antineoplastic; D053477:Apoptotic Protease-Activating Factor 1; D005079:Excipients; D008689:Methacrylates; D011506:Proteins; D004317:Doxorubicin; D020169:Caspases; C032802:hydroxypropyl methacrylate