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

Autor: Shao-jia Wang, Zhaozhi Yang, Xingxing Chen, Yan Feng, Xiaoli Yu, Jurui Luo, Xiaomao Guo, Li Zhang, Zhi-Rui Zhou
Rok vydání: 2016
Předmět:
0301 basic medicine
Radiation-Sensitizing Agents
autophagy
animal structures
DNA damage
human triple-negative breast cancer
Mice
Nude
Triple Negative Breast Neoplasms
Biology
environment and public health
Radiation Tolerance
03 medical and health sciences
0302 clinical medicine
Breast cancer
Radiation tolerance
Cell Line
Tumor
Radiation
Ionizing
medicine
Animals
Humans
Pharmacology (medical)
Radiosensitivity
skin and connective tissue diseases
Protein Kinase Inhibitors
Triple-negative breast cancer
Pharmacology
Mice
Inbred BALB C
checkpoint kinase 1
MK-8776
xenograft tumors
Autophagy
General Medicine
medicine.disease
CHK1 Inhibitor MK-8776
enzymes and coenzymes (carbohydrates)
030104 developmental biology
Pyrimidines
Cell culture
radiosensitivity
030220 oncology & carcinogenesis
Immunology
Cancer research
Pyrazoles
Female
Original Article
biological phenomena
cell phenomena
and immunity
DNA Damage
Zdroj: Acta Pharmacologica Sinica
ISSN: 1745-7254
Popis: 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 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 irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.
Databáze: OpenAIRE
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