Acute overexpression of wt p53 facilitates anticancer drug-induced death of cancer and normal cells.
The relationship between chemosensitivity and p53 is currently considered from two mutually exclusive points of view: (1) wt p53 increases chemosensitivity due to apoptosis and (2) wt p53 decreases chemosensitivity due to growth arrest and DNA repair. We used p53-expressing adenovirus (Ad-p53) to directly evaluate effect of p53 on sensitivity to anticancer drugs. When p53 was expressed at sublethal levels, it sensitized cells to the DNA-damaging drugs Adriamycin, mitomycin C, actinomycin D, etoposide (VP16), cisplatin and CPT11. This sensitization was observed in cancer cell lines (N=10) regardless of endogenous p53 status and also in normal human lung and skin fibroblasts. The degree of sensitization appeared to be greater in cancer cells with mutant p53. Normal fibroblasts required significantly higher doses of Ad-p53 to affect a drug's sensitivity partly because of their lower infectivity by adenovirus. Wt p53 not only decreased IC50 but also accelerated cell death induced by DNA-damaging drugs. In contrast, sensitization to microtubule-active drugs by p53 was shown only in a few cell lines. We conclude that exogenous wt p53 accelerates cell death induced by DNA damaging agents in both normal and cancer cells and offers no protection from anticancer drugs.
Blagosklonny
M V
MV
Medicine Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. mikhailb@box-m.nih.gov
El-Deiry
W S
WS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects*; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage* / Q000502:physiology
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin