HDAC抑制剂及其联合PI3K抑制剂抗肿瘤研究进展

Advances in anti-tumor research of HDAC inhibitors and combination with PI3K inhibitors

组蛋白去乙酰化酶(histone deacetylase, HDAC)通常异常过表达,导致肿瘤抑制基因的转录抑制。作为具有巨大潜力的抗癌药物,组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDIs)可以通过调节核小体结构,抑制HDAC活性,调控抑癌基因表达而发挥抗肿瘤效应。目前,已上市的5个HDAC抑制剂适应症局限于外周T细胞淋巴瘤和皮肤T细胞淋巴瘤,而在实体瘤方面,大多数作为单一药物使用的HDAC抑制剂未能得到有效的治疗效果。磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K)是PI3K-AKT-mTOR信号通路的起始节点,在肿瘤细胞的增殖、迁移、侵袭、分化等过程中起着十分重要的作用,该通路的异常激活与肿瘤的发生发展有着密切关系,将HDAC抑制剂和PI3K抑制剂的联合使用以及HDAC/PI3K双靶点抑制剂能够改善单独用药时存在的问题。本综述介绍了具有代表性的HDIs和PI3K抑制剂,以及HDAC/PI3K抑制剂联用及双靶点抑制剂的抗肿瘤临床和临床前研究进展。

Histone deacetylase(HDAC) is usually abnormally overexpressed,which mainly leads to the transcriptional repression of tumor suppressor genes.Histone deacetylase inhibitors(HDIs) exert anti-tumor biological effects by regulating nucleosome structure,inhibiting HDAC activity,and controlling the expression of tumor suppressor genes.There are currently 5 drugs on the market,but only for peripheral T-cell lymphoma and cutaneous T-cell lymphoma.In solid tumors,most of the HDAC inhibitors used have failed to achieve effective therapeutic effects.Phosphoinositide 3-kinase(PI3K) is the starting node of the PI3K-AKT-mTOR signaling pathway,which plays a very important role in the proliferation,migration,invasion,and differentiation of tumor cells.The abnormal activation of PI3K is closely related to the occurrence and development of tumors,and the combined use of HDAC and PI3K inhibitors and HDAC/PI3K dual-target inhibitors show synergistic anticancer activity.This article introduces the anti-tumor clinical and preclinical research progress of representative HDAC inhibitors and PI3K inhibitors,as well as HDAC/PI3K dual-target inhibitors.