Discovery of homocamptothecin derivative TOP-0618 as a radiosensitive agent for the treatment of pancreatic cancer

Abstract

Abstract Background 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. Methods 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. Results Cytotoxicity assays revealed that IC50 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. Conclusions 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.

Keywords

• Pancreatic cancer
• Radiosensitivity
• TOP-0618
• Homocamptothecin derivative