Targeting cancer-cell mitochondria using Tigecycline improves radiotherapy response in colorectal cancer cell line

Abstract

Background: Colorectal cancer (CRC) is the third most common cancer worldwide and causes more than 50,000 deaths in the United States each year. Due to the limited therapeutic options and poor prognosis in CRC, extensive research and development of novel therapeutic methods is essential. In this regard, the presence of cancer stem cells with unlimited division ability is the main reason for the therapeutic resistance in CRC. Tigecycline is a pharmacological mitochondria inhibitor and blocks mitochondria-related cell proliferation in cancer cells. This study investigated the effects of Tigecycline combined with radiotherapy on CRC cell apoptosis. Methods: Human colorectal cancer cells (HCT-116) were treated with Tigecycline, and cell viability was measured with MTT assay. In the next step, the cells were exposed to radiation using a Siemens Primus 6 MV linear accelerator at radiation dose of 400 cGy. Finally, we evaluated cancer cell apoptosis, caspase-3 activity and apoptotic-related genes expression with AnnexinV/PI, flowcytometry and gene expression, respectively. Results: The MTT assay revealed an IC50 value of 93 mu M for Tigecycline after 48 hours. Mitochondria inhibition, at its IC50 value, sensitizes colorectal cancer cells to radiotherapy. Compared to monotherapy, the combination therapy increased the number of apoptotic cells and caspase-3 activity, up-regulated pro-apoptotic genes, and down-regulated anti-apoptotic genes. Conclusion: In conclusion, our data suggests that targeting mitochondria may represent a clinically relevant approach to enhance the sensitivity of colorectal cancer cells to therapy. These findings could provide new insights into cancer therapy and might be used as a novel method to improve the current state of CRC therapy.