The novel mTORC1/2 dual inhibitor INK128 enhances radiosensitivity of breast cancer cell line MCF-7

Liu,Zhi-Gang; Tang,Jiao; Chen,Zhenghu; Zhang,Huiyuan; Wang,Hui; Yang,Jianhua; Zhang,Hong

doi:10.3892/ijo.2016.3604

The novel mTORC1/2 dual inhibitor INK128 enhances radiosensitivity of breast cancer cell line MCF-7

Authors:
- Zhi-Gang Liu
- Jiao Tang
- Zhenghu Chen
- Huiyuan Zhang
- Hui Wang
- Jianhua Yang
- Hong Zhang
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Affiliations: 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, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA, Department of Pathology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
Published online on: July 5, 2016 https://doi.org/10.3892/ijo.2016.3604
Pages: 1039-1045

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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.

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