Lawson K R, Ignatenko N A, Piazza G A, Cui H, Gerner E W
The University of Arizona, Arizona Cancer Center, Biochemistry Department Tucson 85724, USA.
Cancer Epidemiol Biomarkers Prev. 2000 Nov;9(11):1155-62.
The nonsteroidal anti-inflammatory drug sulindac and the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) are both potent inhibitors of colon carcinogenesis in experimental models of this disease. The combination of these two agents is undergoing evaluation as a strategy for colon cancer chemoprevention in humans with resected colon polyps. We evaluated the effects of the major sulfide and sulfone metabolites of sulindac and DFMO alone, or in combinations, on the growth and survival of Caco-2 colon cancer-derived cells and in clones of these cells transfected with an activated K-ras oncogene. Both the sulfide and sulfone metabolites of sulindac reduced cell viability, measured by colony-forming assays, primarily by inducing apoptosis. Expression of an activated K-ras oncogene caused cells treated with either sulindac sulfide or sulfone to undergo apoptosis earlier than nontransfected controls. However, clonogenic survival, measured 2 weeks after drug treatment, was the same in both Caco-2 and ras-transfected Caco-2 cells treated with sulindac metabolites. A 24-h treatment with DFMO caused a dose-dependent decrease in the colony-forming ability of cells expressing an activated K-ras but had no effect on the viability of the parental Caco-2 cells. The DFMO-dependent decrease in colony formation in K-ras-activated cells occurred in the absence of apoptosis. Assessment of cell survival by colony-forming assays indicated that these two agents acted in an additive manner when combined. These data indicate that K-ras can influence the kinetics of apoptosis induction by sulindac metabolites and cell survival in response to DFMO. However, cytotoxicity induced by these agents occurs via unique mechanisms. These studies suggest that the combination of DFMO and sulindac may be useful in human cancer prevention strategies.
非甾体抗炎药舒林酸和鸟氨酸脱羧酶抑制剂二氟甲基鸟氨酸（DFMO）在结肠癌的实验模型中都是结肠癌发生的有效抑制剂。这两种药物的联合正在作为一种对已切除结肠息肉的人类进行结肠癌化学预防的策略进行评估。我们评估了舒林酸和DFMO的主要硫化物和砜代谢物单独或联合使用对Caco-2结肠癌细胞及其转染了活化K-ras癌基因的细胞克隆的生长和存活的影响。舒林酸的硫化物和砜代谢物均通过集落形成试验测定降低细胞活力，主要是通过诱导细胞凋亡。活化K-ras癌基因的表达导致用舒林酸硫化物或砜处理的细胞比未转染的对照更早地发生凋亡。然而，在用舒林酸代谢物处理的Caco-2细胞和ras转染的Caco-2细胞中，药物处理2周后测得的克隆形成存活率是相同的。用DFMO处理24小时导致表达活化K-ras的细胞的集落形成能力呈剂量依赖性下降，但对亲代Caco- cells细胞的活力没有影响。在K-ras活化细胞中，DFMO依赖性的集落形成减少在没有细胞凋亡的情况下发生。通过集落形成试验评估细胞存活表明，这两种药物联合使用时以相加的方式起作用。这些数据表明，K-ras可以影响舒林酸代谢物诱导细胞凋亡的动力学以及对DFMO的细胞存活反应。然而，这些药物诱导的细胞毒性是通过独特的机制发生的。这些研究表明，DFMO和舒林酸的联合可能对人类癌症预防策略有用。
