Tang Yin, Huang Chengyi, Chen Di, Gong Yangyang, Chen Liang, Chen Wenjuan, You Liang, Miao Zhenyuan, Zhang Huojun
Department of Radiation Oncology, Changhai Hospital affiliated to Naval Medical University, Shanghai, 200433, China.
Department of Gastroenterology, The 83 rd Group Army Hospital, 83 rd Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453000, China.
BMC Cancer. 2025 May 25;25(1):936. doi: 10.1186/s12885-025-14347-x.
Pancreatic cancer is one of the most lethal malignancies characterized by a complex tumor microenvironment (TME) and highly heterogeneous nature, making it resistant to radiotherapy. This study aims to evaluate the radiosensitizing effect of homocamptothecin derivative TOP-0618 on pancreatic cancer.
Clonogenic assays and cell viability assays were used to evaluate the radiosensitizing effects of TOP-0618 on pancreatic cancer cells. Cell cycle and apoptosis were detected using flow cytometry. A pancreatic bi-flank xenograft tumor model was used to evaluate the radiosensitivity of TOP-0618. H&E staining analyses and TUNEL staining were used to examine necrosis and apoptosis of pancreatic xenograft tumors.
Cytotoxicity assays revealed that IC values of TOP-0618 against PANC-1 and MIAPaCa-2 cells were 1.442 µmol/L and 1.198 µmol /L, respectively. Additionally, clonogenic assays revealed that TOP-0618 exerted radiosensitizing effects on both pancreatic cells, and the sensitizer enhancement ratio (SER) of TOP-0618 was 1.14 for the PANC-1 cell line and 1.65 for the MIAPaCa-2 cell line. The preliminary study revealed that TOP-0618 improved radiosensitivity by enhancing G2/M phase arrest and increasing the apoptosis of pancreatic cells. Subsequently, in a pancreatic bi-flank xenograft tumor model, TOP-0618 combined with irradiation significantly inhibited tumor growth, and increased necrosis and apoptosis in pancreatic xenograft tumors.
Our work demonstrates the radiosensitizing effect of homocamptothecin derivative TOP-0618 on pancreatic cancer both in vivo and vitro, and lays a foundation for clinical transformation.
胰腺癌是最致命的恶性肿瘤之一，其特征是肿瘤微环境复杂且具有高度异质性，这使其对放疗具有抗性。本研究旨在评估喜树碱衍生物TOP-0618对胰腺癌的放射增敏作用。
采用克隆形成试验和细胞活力试验评估TOP-0618对胰腺癌细胞的放射增敏作用。使用流式细胞术检测细胞周期和凋亡情况。采用胰腺双侧异种移植瘤模型评估TOP-0618的放射敏感性。通过苏木精-伊红（H&E）染色分析和TUNEL染色检测胰腺异种移植瘤的坏死和凋亡情况。
细胞毒性试验显示，TOP-0618对PANC-1和MIAPaCa-2细胞的半数抑制浓度（IC）分别为1.442 μmol/L和1.198 μmol/L。此外，克隆形成试验表明，TOP-0618对两种胰腺癌细胞均具有放射增敏作用，TOP-0618对PANC-1细胞系的增敏增强率（SER）为1.14，对MIAPaCa-2细胞系为1.65。初步研究表明，TOP-0618通过增强G2/M期阻滞和增加胰腺细胞凋亡来提高放射敏感性。随后，在胰腺双侧异种移植瘤模型中，TOP-0618联合放疗显著抑制肿瘤生长，并增加胰腺异种移植瘤的坏死和凋亡。
我们的研究证明了喜树碱衍生物TOP-0618在体内和体外对胰腺癌均具有放射增敏作用，为临床转化奠定了基础。
