Crescenzi Elvira, Palumbo Giuseppe, Brady Hugh J M
Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università di Napoli Federico II, Naples, Italy.
Clin Cancer Res. 2005 Nov 15;11(22):8158-71. doi: 10.1158/1078-0432.CCR-05-1042.
Treatment of tumor cells by chemotherapy activates a series of responses ranging from apoptosis to premature senescence and repair. Survival responses are characterized by inhibition of cyclin-dependent kinases. Because inhibition of cyclin-dependent kinases represents a distinctive feature of DNA damage-induced prosurvival responses, we investigated the possibility that the cyclin-dependent kinase inhibitor roscovitine modulates drug-induced responses in human adenocarcinoma cells, favoring cell survival.
Sublethal concentrations of doxorubicin were used to induce premature senescence in human adenocarcinoma cells. The effect of the cyclin-dependent kinase inhibitor roscovitine on the doxorubicin-dependent cell cycle checkpoint activation and DNA repair pathways was evaluated.
Roscovitine reinforces doxorubicin-dependent G(1) checkpoint in A549 and HEC1B cells leading to decreased frequency of double-strand breaks and to the preferential induction of senescence and enhanced clonogenic survival. However, in other tumor cell lines, such as HCT116 and H1299, combined treatment with doxorubicin and roscovitine increases the frequency of double-strand breaks and dramatically sensitizes to doxorubicin. This unexpected effect of roscovitine depends on a novel ability to inhibit DNA double-strand break repair processes and requires inactivation of the pRb pathway.
Roscovitine, by hindering DNA repair processes, has the potential to inhibit recovery of mildly damaged tumor cells after doxorubicin treatment and to increase the susceptibility of tumor cells to chemotherapy. However, in some tumor cells, the cell cycle inhibitory function of roscovitine prevails over the DNA repair inhibitory activity, favoring premature senescence and clonogenic growth. These data indicate a novel mechanism underlying combined chemotherapy, which may have wide application in treatment of carcinomas.
通过化疗治疗肿瘤细胞会激活一系列反应，从细胞凋亡到过早衰老和修复。存活反应的特征是细胞周期蛋白依赖性激酶受到抑制。由于抑制细胞周期蛋白依赖性激酶是DNA损伤诱导的促存活反应的一个显著特征，我们研究了细胞周期蛋白依赖性激酶抑制剂罗可辛调节人腺癌细胞中药物诱导反应、促进细胞存活的可能性。
使用亚致死浓度的阿霉素诱导人腺癌细胞过早衰老。评估细胞周期蛋白依赖性激酶抑制剂罗可辛对阿霉素依赖性细胞周期检查点激活和DNA修复途径的影响。
罗可辛增强了阿霉素在A549和HEC1B细胞中依赖性的G(1)检查点，导致双链断裂频率降低，并优先诱导衰老和增强克隆形成存活能力。然而，在其他肿瘤细胞系中，如HCT116和H1299，阿霉素与罗可辛联合治疗会增加双链断裂频率，并显著增强对阿霉素的敏感性。罗可辛的这种意外作用取决于其抑制DNA双链断裂修复过程的新能力，并且需要pRb途径失活。
罗可辛通过阻碍DNA修复过程，有可能抑制阿霉素治疗后轻度受损肿瘤细胞的恢复，并增加肿瘤细胞对化疗的敏感性。然而，在某些肿瘤细胞中，罗可辛的细胞周期抑制功能超过了DNA修复抑制活性，有利于过早衰老和克隆生长。这些数据表明联合化疗存在一种新机制，可能在癌症治疗中有广泛应用。
