Hata Taishi, Yamamoto Hirofumi, Ngan Chew Yee, Koi Minoru, Takagi Akimitsu, Damdinsuren Bazarragchaa, Yasui Masayoshi, Fujie Yujiro, Matsuzaki Takeshi, Hemmi Hiromichi, Xu Xundi, Kitani Kotaro, Seki Yosuke, Takemasa Ichiro, Ikeda Masataka, Sekimoto Mitsugu, Matsuura Nariaki, Monden Morito
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan.
Mol Cancer Ther. 2005 Oct;4(10):1585-94. doi: 10.1158/1535-7163.MCT-05-0011.
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-/- were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21waf1/cip1 induction and G0-G1 arrest in p53 wild-type cells, whereas cisplatin did not induce G0-G1 arrest. Assays using p53 wild but p21waf1/cip1 null HCT116 cells revealed that oxaliplatin did not show G0-G1 arrest and reduced growth-inhibitory effects, suggesting that p21waf1/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 p21waf1/cip1-mediated growth inhibition and G0-G1 arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G1 to S phase and eventually resulted in G2-M arrest. This abrupt entry into S phase was associated with loss of the p21waf1/cip1 protein via proteasome-mediated degradation. These findings suggest that p21waf1/cip1 plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways.
临床研究表明，新型铂衍生物奥沙利铂与5-氟尿嘧啶和亚叶酸联合使用时，是一种有效的结直肠癌化疗药物。尽管其毒性活性基于铂与DNA之间的共价加合物，但其实际生物学行为大多未知。为了探索肿瘤对奥沙利铂敏感性的机制，我们参照p53基因状态研究了奥沙利铂对结直肠癌细胞系的细胞毒性作用。尽管p53基因状态并不能明确预测对奥沙利铂的敏感性，但包括HCT116在内的p53野生型细胞对奥沙利铂敏感，而HCT116 p53 -/-细胞对奥沙利铂耐药。奥沙利铂在p53野生型细胞中引起强烈的p21waf1/cip1诱导和G0-G1期阻滞，而顺铂未诱导G0-G1期阻滞。使用p53野生但p21waf1/cip1缺失的HCT116细胞进行的实验表明，奥沙利铂未显示G0-G1期阻滞且生长抑制作用减弱，这表明p21waf1/cip1可能是奥沙利铂处理的p53野生型细胞中的关键因素。尽管HCT116存在DNA错配修复缺陷，但错配修复功能正常的HCT116+ch3细胞系在p21waf1/cip1介导的生长抑制和G0-G1期阻滞方面表现出相似的反应。另一方面，在p53突变细胞中，奥沙利铂导致细胞从G1期突然过渡到S期，并最终导致G2-M期阻滞。这种突然进入S期与通过蛋白酶体介导的降解导致p21waf1/cip1蛋白丢失有关。这些发现表明，p21waf1/cip1在奥沙利铂介导的p53依赖性和非依赖性途径的细胞周期和生长控制中发挥作用。
