Time- and concentration-dependent apoptosis and necrosis induced by free and HPMA copolymer-bound doxorubicin in human ovarian carcinoma cells.
A2780 sensitive and A2780/AD doxorubicin (DOX) resistant human ovarian carcinoma cells were exposed to different concentrations (0.25, 0.5, 1, 5 and 10xIC(50)) of free and HPMA copolymer-bound DOX for 12, 24, 36, 48, 60 and 72 h. Apoptosis and necrosis were evaluated using the FITC-conjugated annexin V and propidium iodide staining. The data obtained showed that the induction of apoptosis and necrosis by both free DOX and HPMA copolymer-bound DOX were time- and concentration-dependent. The data also showed significant differences between the drugs. It was found that: (i) under the action of HPMA copolymer-bound doxorubicin the alterations in the plasma membrane permeability preceded disturbances in cellular metabolism; (ii) HPMA copolymer-bound doxorubicin kills the cells mainly by necrosis; (iii) HPMA copolymer-bound doxorubicin is a more effective anticancer drug than free doxorubicin.
Demoy
M
M
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Minko
T
T
Kopecková
P
P
Kopecek
J
J
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002463:Cell Membrane Permeability / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology*; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D008689:Methacrylates / Q000737:chemistry*; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010718:Phosphatidylserines / Q000737:chemistry; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D008689:Methacrylates; D010718:Phosphatidylserines; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate