The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy

• 来源期刊: 中国药理学报（英文版）
• 关键词: human triple-negative breast cancer checkpoint kinase 1 MK-8776 radiosensitivity autophagy xenograft tumors
• 年，卷（期）: 2017,（4）
• 页码范围: 513-523
• 页数: 11页
• 语种: 英文
• DOI: 10.1038/aps.2016.136

摘要

MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1),which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization.A number of studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities.Thus far,there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent.In this study,we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231,BT-549 and CAL-51.MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231,BT-549 and CAL-51 cells with IC50 values of 9.4,17.6 and 2.1 μmol/L,respectively.Compared with irradiation-alone treatment,pretreatment with a low dose of MK-8776 (100-400 nmol/L) significantly increased irradiation-induced yH2A.X foci in the 3 TNBC cell lines,suggesting enhanced DNA damage by MK-8776,inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines.Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg,ip) 26 d after irradiation.To explore the mechanisms underlying the radio-sensitization by MK-8776,we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines.Moreover,irradiation markedly elevated the levels of Atg5,and promoted the transformation of LC3-Ⅰ to LC3-Ⅱ in the cells.Pretreatment with the low dose of MK-8776 suppressed these effects.The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiationinduced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.