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

Abstract

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 HCT116 p53 À/À were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21 waf1/cip1 induction and G 0 -G 1 arrest in p53 wild-type cells, whereas cisplatin did not induce G 0 -G 1 arrest. Assays using p53 wild but p21 waf1/cip1 null HCT116 cells revealed that oxaliplatin did not show G 0 -G 1 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 G 0 -G 1 arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G 1 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 p21 waf1/cip1 plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways. [Mol Cancer Ther 2005;4(10):1585 -94]

Antitumor activity of electrospun polylactide nanofibers loaded with 5-fluorouracil and oxaliplatin against colorectal cancer

“…A total of 50.6% of HCT-8 cells incubated with O + F/fiber were arrested at the G0/G1 phase relative to 54.4% of free drugs at 24 h postincubation, whereas only 44.97% and 44.29% of cells in empty PLLA fiber group and control group were arrested at the G0/G1 phase (p50.05). The above results were in agreement with the previous studies (Hata et al, 2005), which showed that in a p53-dependent pathway, oxaliplatin enhanced the expression of p21waf1/cip1 protein, which may be responsible for the growth-inhibitory activity by delaying the transition from G0/G1 to S phase in HCT-116 human colorectal cells.…”

Role of p21 as a determinant of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane response in human HCT-116 colon carcinoma cells

“…HCT-116 p53 -/-and HCT-116 p21 -/-cells lost both the growth-inhibitory effect and G 0 /G 1 arrest pattern of the cell cycle after DPD treatment. Previous studies have also shown the p21 induction and G 1 arrest by a p53-independent pathway (22) and the p21 involvement in cell growth and cell cycle of HCT-116 cells (23)(24)(25). It has been suggested that DPD induces p21 expression through a p53-independent pathway in colon cancer cells.…”

Comparison of oxaliplatin‐ and curcumin‐mediated antiproliferative effects in colorectal cell lines

“…Oxaliplatin and curcumin are known to cause G2/M cell cycle arrest in some cell lines, [16][17][18] which may account for the decrease in proliferative capacity following treatments with these agents, both singly and combined in the 2 colon tumor cell lines.…”