[Roles of p53 in adriamycin-induced cell death and in acquisition of adriamycin resistance in adult T-cell leukemia (ATL) cells].
In order to define the roles of p53 in acquisition of drug resistance in ATL cell lines, we prepared several ATL cell lines which differed in sensitivity to adriamycin (ADM), and examined their functional p53 statuses, expressions of p53, p21, Bcl-2, Bax, and cell cycles. Our findings demonstrated: (1) Regardless of sensitivity to ADM, most of the cell lines, including ADM-resistant cell lines, carried wild-type p53. (2) Only one cell line, ED-S, which was the most sensitive to ADM carried non-functional mutated-type p53. (3) In the ATL cells carrying wild-type p53, regardless of sensitivity to ADM, ADM-treatment led to an elevation of p53 protein level with concomitant elevations of p21 and Bax protein levels. (4) In the cell line expressing mutated-type p53, ADM-treatment at the concentration of IC50 induced elevations of p53, and Bax protein levels but did not p21 protein level. (5) Expression of Bcl-2 protein did not change in any of the cell lines by treatment with ADM at their respective IC50 levels, but increased in the ADM-resistant cell line when it was treated with ADM at IC50 of its parent cell line. (6) In the cell cycle analysis, ADM-treatment induced G1- and G2-arrest and then apoptosis in the cell lines with wild-type p53, whereas it induced only G2-arrest and then apoptosis in the cell line with mutated-type p53 at the same time course as in those with wild-type p53. These findings suggest that p53 does not play a leading part either in the apoptosis induced by ADM, or in the acquisition of resistance to ADM in ATL cells, and that ADM-induced apoptosis is mediated by multiple pathways leading to the activation of effector molecules.
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Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin