Role of p21waf1/cip1 in effects of oxaliplatin in colorectal cancer cells

Clinical studies have shown that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent for colorectal cancer when combined with 5-fluorouracil and leucovorin. Although the toxic activity is based on covalent adducts between platinum and DNA, its actual biological behavior is mostly unknown. In an effort to explore the mechanism of tumor susceptibility to oxaliplatin, we examined the cytotoxic effects of oxaliplatin in colorectal cancer cell lines in reference to p53 gene status. Although p53 gene status did not clearly predict sensitivity to oxaliplatin, p53 wild-type cells including HCT116 were sensitive but HCT1 16 p53(-/-) were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21(waf1/cip1) induction and Go-G, arrest in p53 wild-type cells, whereas cisplatin did not induce GO-G, arrest. Assays using p53 wild but p21(waf1/cip1) null HCT1 16 cells revealed that oxaliplatin did not show Go-G, arrest and reduced growth-inhibitory effects, suggesting that p21(waf1/cip1) may be a key element in oxaliplatin-treated p53 wild-type cells. Although HCT116 is DNA mismatch repair -deficient, a mismatch repair-proficient HCT116+ch3 cell line displayed similar responses with regard to p21(waf1/cip1)-mediated growth inhibition and GO-G, arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G, to S phase and eventually resulted in G(2)-M arrest. This abrupt entry into S phase was associated with loss of the p21(waf1/cip1) protein via proteasome-mediated degradation. These findings suggest that p2lwafl/cipi plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways.