Histone deacetylase inhibitors specifically kill nonproliferating tumour cells
Histone deacetylase inhibitors specifically kill nonproliferating tumour cells
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DOI：
10.1038/sj.onc.1207893
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发表时间：
2004-09-02
期刊：
影响因子：
8
通讯作者：
Gabrielli, B
中科院分区：
文献类型：
--
作者：
Burgess, A;Ruefli, A;Gabrielli, B
传统的化疗药物以增殖细胞为目标，依靠肿瘤细胞与正常组织相比药物敏感性的微小差异来提供治疗效果。因此，与快速增殖的肿瘤细胞相比，它们具有显著的限制性毒性和对非增殖的功效大大降低。缺乏选择性和无法杀死存在于低有丝分裂指数肿瘤中的非增殖细胞是这些药物的主要缺陷。一种相对较新的抗癌药物，组蛋白去乙酰化酶抑制剂（HDI），具有选择性细胞毒性，可以杀死肿瘤细胞和永生细胞，但正常组织似乎具有耐药性。用这些药物治疗肿瘤细胞会引起与p21表达增加相关的G1期细胞周期阻滞和细胞死亡，但即使是G1期阻滞的细胞也会死亡，尽管死亡的开始被推迟。我们通过血清饥饿或表达周期蛋白依赖性激酶抑制剂p16（ink4a）来稳定地抑制细胞，扩展了这些观察结果。我们报道，组蛋白去乙酰化酶抑制剂对增殖和阻滞的肿瘤细胞和永生化细胞具有相似的细胞毒性，尽管阻滞细胞的凋亡发作延迟了24小时。增殖和阻滞的正常细胞都不受HDI治疗的影响。因此，组蛋白去乙酰化酶抑制剂是一类抗癌药物，具有作为肿瘤选择性细胞毒性药物的理想特征，在杀死增殖和非增殖肿瘤细胞以及永生化细胞方面同样有效。这些药物不仅对快速增殖的肿瘤有巨大的治疗潜力，而且对有丝分裂指数低的肿瘤也有巨大的治疗潜力。
Conventional chemotherapeutic drugs target proliferating cells, relying on often small differences in drug sensitivity of tumour cells compared to normal tissue to deliver a therapeutic benefit. Consequently, they have significant limiting toxicities and greatly reduced efficacy against nonproliferating compared to rapidly proliferating tumour cells. This lack of selectivity and inability to kill nonproliferating cells that exist in tumours with a low mitotic index are major failings of these drugs. A relatively new class of anticancer drugs, the histone deacetylase inhibitors (HDI), are selectively cytotoxic, killing tumour and immortalized cells but normal tissue appears resistant. Treatment of tumour cells with these drugs causes both G1 phase cell cycle arrest correlated with increase p21 expression, and cell death, but even the G1 arrested cells died although the onset of death was delayed. We have extended these observations using cells that were stably arrested by either serum starvation or expression of the cyclin-dependent kinase inhibitor p16(ink4a). We report that histone deacetylase inhibitors have similar cytotoxicity towards both proliferating and arrested tumour and immortalized cells, although the onset of apoptosis is delayed by 24 h in the arrested cells. Both proliferating and arrested normal cells are unaffected by HDI treatment. Thus, the histone deacetylase inhibitors are a class of anticancer drugs that have the desirable features of being tumour-selective cytotoxic drugs that are equally effective in killing proliferating and nonproliferating tumour cells and immortalized cells. These drugs have enormous potential for the treatment of not only rapidly proliferating tumours, but tumours with a low mitotic index.