Casein Kinase ۱ Alpha Inhibitor (D۴۴۷۶) Sensitizes Microsatellite Instable Colorectal Cancer Cells to ۵-FU

Introduction: Chemotherapy is the commonly used therapeutic approach in colon cancer therapy, leading to extended survival rates in the patients. ۵-FU is the most frequently used medication in the treatment of colorectal cancer (CRC), however, more than ۴۰% of cases with microsatellite instability (MSI-H) are resistant to ۵-FU. Accumulated research indicates that ATP-binding cassette (ABC) transporters (e.g., ABCG۲), autophagy and cell cycle regulators (e.g., cyclin D۱ and c-myc) are well-known mechanisms that contribute to drug resistance in cancer. Considering that key signaling pathways known to be critically involved in tumor progression and autophagy are regulated by casein kinase ۱ alpha (CK۱α), we attempted to elucidate the combined effect of ۵-FU and CK۱α inhibitor (D۴۴۷۶) on HCT۱۱۶ cells as a model of high level of microsatellite instability (MSI-H) colorectal cancer. Methods: To achieve this goal, the gene expression of MDR related genes (ABCG۲, cyclin D۱ and c-myc) were analyzed by quantitative real time polymerase chain reaction. Results: Our results show that the combination of ۵-FU/ D۴۴۷۶ decreased the gene expression of ABCG۲, cyclin D۱ and c-myc compared with the use of ۵-FU alone. Conclusion: To the best of our knowledge, this study indicates for the first time that CK۱α inhibitor (D۴۴۷۶) could potentially sensitize HCT۱۱۶ cells to ۵-FU chemotherapy agent. Additionally, combination of ۵-FU/D۴۴۷۶ may facilitate the effectiveness of the treatment protocols.

کلیدواژه ها:

۵-Fluorouracil ، CK۱α inhibitor ، Colorectal cancer ، Combination treatment ، Chemoresistance