Evaluation of anti-tumor activity of borated camptothecin derivatives targeting topoisomerase 1 against hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Objectives Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is a common malignancy lacking effective chemotherapies. Camptothecin (CPT) derivatives, though approved for treatment, face limitations due to systemic toxicity. Boration has been shown to improve drug bioavailability and reduce toxicity. We designed and synthesized a new 9-borate CPT derivative, CPT-01, to evaluate its anti-tumor potential. Methods In vitro assays, including EdU incorporation, colony formation, and flow cytometry, assessed CPT-01's effects on proliferation, apoptosis, and cell cycle. AKT/Ras- and AKT/NICD-induced primary mouse models of HCC and ICC were used for in vivo evaluation. Molecular mechanisms were explored using western blotting, immunohistochemistry, topoisomerase I inhibition assays, and molecular docking. Results CPT-01 exhibited stronger anti-tumor activity than topotecan (TPT) in both cancer cell lines and mouse models. In vivo , it showed greater efficacy in AKT/Ras-induced HCC and AKT/NICD-induced ICC models, with no significant toxicity at therapeutic doses. Mechanistically, CPT-01 inhibited topoisomerase I, inducing DNA damage, cell cycle arrest, and apoptosis. Conclusions CPT-01 demonstrates enhanced anti-tumor efficacy and reduced toxicity compared to TPT, offering promising clinical potential for liver cancer treatment.