Ma Junjie, Wu Shanshan, Yang Xinxin, Shen Shuying, Zhu Yiqian, Wang Ruoqi, Xu Wei, Li Yue, Zhu Haixin, Yan Youyou, Lin Nengming, Zhang Bo
School of Pharmaceutical Sciences, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou, Zhejiang, China.
Front Pharmacol. 2025 Mar 25;16:1557925. doi: 10.3389/fphar.2025.1557925. eCollection 2025.
Colorectal cancer (CRC) ranks as the third most common cancer globally. Neoadjuvant radiotherapy is the standard treatment for locally advanced rectal cancer; however, primary or acquired resistance often leads to treatment failure. Identifying new targets to overcome radiotherapy resistance in CRC is crucial for improving patient outcomes.
To evaluate the antitumor effects of Milciclib in CRC cells, we conducted assays measuring cell viability, cell cycle progression, and apoptosis in HCT116 and RKO cell lines following Milciclib treatment. Additionally, CRC cells were treated with a combination of Milciclib and irradiation to determine whether Milciclib could enhance their radiosensitivity. The efficacy of Milciclib was also assessed in radiation-resistant CRC cells.
The results of cytotoxicity and proliferation assays indicated that the IC50 values of Milciclib for human colorectal cancer cell lines HCT-116 and RKO, based on cell viability measurements, were 0.275 μM and 0.403 μM, respectively. Milciclib induced a dose-dependent reduction in the proportion of CRC cells in the G2/M phase and promoted apoptosis. When combined with irradiation, Milciclib led to a 20% increase in the proportion of cells in the G1 phase and a 10% decrease in the G2 phase, suggesting an alteration in cell cycle distribution. Additionally, Milciclib impaired DNA damage repair by inhibiting Rad51, thereby enhancing radiation sensitivity. In radiation-resistant CRC cells, the combination of Milciclib and irradiation demonstrated increased efficacy, with a sensitizer enhancement ratio (SER) above 1, indicating a potential radiosensitizing effect.
Milciclib exhibits antitumor activity in CRC cells as a monotherapy and enhances the effectiveness of radiotherapy when used in combination. It disrupts the G2/M checkpoint and impairs DNA repair mechanisms. These findings suggest that Milciclib has the potential to be an effective therapeutic agent for CRC.
结直肠癌（CRC）是全球第三大常见癌症。新辅助放疗是局部晚期直肠癌的标准治疗方法；然而，原发性或获得性耐药常常导致治疗失败。确定新的靶点以克服结直肠癌的放疗耐药性对于改善患者预后至关重要。
为了评估米西立滨对结直肠癌细胞的抗肿瘤作用，我们进行了实验，检测米西立滨处理后HCT116和RKO细胞系的细胞活力、细胞周期进程和凋亡情况。此外，用米西立滨和辐射联合处理结直肠癌细胞，以确定米西立滨是否能增强其放射敏感性。还在耐辐射的结直肠癌细胞中评估了米西立滨的疗效。
细胞毒性和增殖实验结果表明，基于细胞活力测量，米西立滨对人结直肠癌细胞系HCT - 116和RKO的IC50值分别为0.275 μM和0.403 μM。米西立滨诱导G2/M期结直肠癌细胞比例呈剂量依赖性降低，并促进凋亡。与辐射联合使用时，米西立滨使G1期细胞比例增加20%，G2期细胞比例减少10%，表明细胞周期分布发生改变。此外，米西立滨通过抑制Rad51损害DNA损伤修复，从而增强放射敏感性。在耐辐射的结直肠癌细胞中，米西立滨与辐射联合使用显示出更高的疗效，增敏比（SER）大于1，表明具有潜在的放射增敏作用。
米西立滨作为单一疗法在结直肠癌细胞中表现出抗肿瘤活性，联合使用时可增强放疗效果。它破坏G2/M检查点并损害DNA修复机制。这些发现表明米西立滨有潜力成为一种有效的结直肠癌治疗药物。
