title: The novel mTORC1/2 dual inhibitor INK128 enhances radiosensitivity of breast cancer cell line MCF-7.
abstract: mTOR, a member of the PIKK family, is crucial for cell growth, survival, motility, proliferation, protein synthesis and DNA transcription. Many studies have demonstrated that mTOR inhibitor could enhance radiosensitivity. However, the effect of the novel mTORC1/2 dual inhibitor, INK128, on the radiosensitivity of breast cancer and the underlying mechanisms are still vague. In the present study, the cell viability was estimated using CCK-8 assay, and the dose-survival relationship was analyzed using a clonogenic survival assay. Cell cycle was evaluated by flow cytometry. The staining of γH2AX foci was assessed by immunofluorescence. In addition, we used western blots to verify the downregulating signal protein and to detect the potential related pathway. We found that the exposure of MCF-7 cells to INK128 decreased the cell viability. Exposure of MCF-7 cells to INK128 and combined ionizing radiation greatly reduced the survival rate. INK128 combined radiotherapy significantly induced G2/M arrest, double strand breaks and inhibited its repair. Furthermore, INK128 plus radiation downregulated p-Chk2, p21 and upregulated cleaved PARP, LC3B expression. These findings suggest that mTOR inhibitor could be used as a novel radiosensitizing target for breast cancer patients.
authors: Key Laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Zhi-Gang
authors: ZG
authors: Liu
authors: Key Laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Jiao
authors: J
authors: Tang
authors: Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Zhenghu
authors: Z
authors: Chen
authors: Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Huiyuan
authors: H
authors: Zhang
authors: Key Laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
authors: Hui
authors: H
authors: Wang
authors: Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Jianhua
authors: J
authors: Yang
authors: Department of Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
authors: Hong
authors: H
authors: Zhang
mesh_terms: D001583:Benzoxazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D018797:Cell Cycle Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D058570:TOR Serine-Threonine Kinases; C572449:sapanisertib; D000225:Adenine