Alteration in p53 pathway and defect in apoptosis contribute independently to cisplatin-resistance

Abstract

The accumulation of molecular genetic defects selected during the adaptation process in the development of cisplatin-resistance was studied using progressive cisplatin-resistant variants (L1210/DDP₂, L1210/DDP₅, L1210/DDP₁₀) derived from a murine leukemia cell line (L1210/0). Of these cell lines, only the most resistant L1210/DDP₁₀ was cross-resistant to etoposide and deficient in apoptosis induced by these two drugs, indicating that resistance to DNA-damaging agents correlates with a defect in apoptosis. This defect was tightly associated with the loss of a Ca²⁺/Mg²⁺-dependent nuclear endonuclease activity present in the less cisplatin-resistant cells. Evidence is presented that p53-dependent function (a) is lost not only in the apoptosis defective L1210/DDP₁₀ cells, but also in the apoptosis susceptible L1210/DDP₅ cells; (b) is unrelated to drug-induced cell cycle pertubations. These results suggest that deficiency in the p53 pathway and resistance to DNA-damaging agents due to a defect in apoptosis are independent events.

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