Department of Radiation Oncology, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C.
Division of General Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C.
Anticancer Res. 2023 May;43(5):1933-1941. doi: 10.21873/anticanres.16353.
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.
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.
The combination of LEE011 and SN38 elicited a synergistic antiproliferative effect on HT-29 (PIK3CA mutation) cells, and an antagonistic antiproliferative effect on SW480 (KRAS mutation) cells. LEE011 inhibited retinoblastoma protein (Rb) phosphorylation and led to G 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 G 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.
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.
背景/目的：结直肠癌（CRC）是全球最常见的恶性肿瘤之一，也是癌症相关死亡的主要原因。联合使用具有不同作用机制的化疗药物可以增强治疗效果并延缓耐药性的发展。本研究旨在探讨瑞博西尼（LEE011）联合伊立替康（SN38）对 CRC 细胞的抗癌作用。
采用 LEE011、SN38 或 LEE011 和 SN38 联合处理 HT-29 和 SW480 细胞，分析细胞活力和细胞周期分布，采用 Western blot 检测细胞周期和凋亡相关蛋白的表达。
LEE011 和 SN38 联合对 HT-29（PIK3CA 突变）细胞表现出协同的增殖抑制作用，对 SW480（KRAS 突变）细胞则表现出拮抗的增殖抑制作用。LEE011 抑制视网膜母细胞瘤蛋白（Rb）磷酸化并导致 HT-29 和 SW480 细胞 G1 期阻滞。SN38 处理导致 SW480 细胞中 Rb、周期蛋白 B1 和 CDC2 的磷酸化水平显著增加，诱导 S 期阻滞。此外，SN38 处理增加了 HT-29 和 SW480 细胞中 p53 的磷酸化水平，并激活了 caspase-3 和 caspase-8。LEE011 诱导的 G1 期阻滞通过下调 Rb 的磷酸化水平，促进了其与 SN38 在 HT-29 细胞中的协同增殖抑制作用。此外，它通过改变 Rb 的磷酸化水平并激活 caspase-8，在 SW480 细胞中与 SN38 产生拮抗作用。
LEE011 与常规化疗药物联合对 CRC 的作用取决于化疗药物和肿瘤细胞中特定的基因突变。
