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

   
@article{APS9557,
	author = {Zhi-rui ZHOU and Zhao-zhi YANG and Shao-jia WANG and Li ZHANG and Ju-rui LUO and Yan FENG and Xiao-li YU and Xing-xing CHEN and Xiao-mao GUO},
	title = {The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy},
	journal = {Acta Pharmacologica Sinica},
	volume = {38},
	number = {4},
	year = {2017},
	keywords = {},
	abstract = {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 triplenegative 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 γH2A.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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/9557}
}