Synergistic and Antagonistic Antiproliferative Effects of Ribociclib (Lee011) and Irinotecan (SN38) on Colorectal Cancer Cells

Abstract

Background/Aim: Colorectal cancer (CRC) is one of the most common malignancies and cause of cancer-related deaths worldwide. The combination of chemotherapeutics working with different mechanisms enhances the therapeutic effects and delays the development of resistance. This study investigated the anticancer effect of the combination of ribociclib (LEE011) and irinotecan (SN38) on CRC cells. Materials and Methods: HT-29 and SW480 cells were treated with LEE011, SN38, or the combination of LEE011 and SN38. Cell viability and cell cycle distribution were analyzed. The expression of cell cycle- and apoptosis-related proteins was determined using western blot. Results: The combination of LEE011 and SN38 elicited a synergistic antiproliferative effect on HT-29 (PIK3CA^P449T mutation) cells, and an antagonistic antiproliferative effect on SW480 (KRAS^G12V mutation) cells. LEE011 inhibited retinoblastoma protein (Rb) phosphorylation and led to G₁ arrest in HT-29 and SW480 cells. SN38 treatment caused a significant increase in the phosphorylation levels of Rb, cyclin B1, and CDC2 in SW480 cells and induced S phase arrest. Furthermore, SN38 treatment increased the phosphorylation levels of p53 and activated caspase-3 and caspase-8 in HT-29 and SW480 cells. LEE011-induced G₁ arrest contributed to its synergistic antiproliferative effect with SN38 in HT-29 cells through the down-regulation of the phosphorylation of Rb. In addition, it elicited an antagonistic effect with SN38 in SW480 cells by changing the phosphorylation levels of Rb and activating caspase-8. Conclusion: The effects of the combination of LEE011 and conventional chemotherapy drugs on CRC depend on the chemotherapy drug and the specific gene mutation harbored by tumor cells.