C118P, a novel microtubule inhibitor with anti-angiogenic and vascular disrupting activities, exerts anti-tumor effects against hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), a hypervascular solid tumor, is the most leading cause of cancer mortality worldwide. Microtubule binding agents targeting tumor vasculature have been investigated and employed clinically. C118P is a newly synthesized analog of CA4 with improved water solubility and extended half-life. The current studies investigated the pharmacological effects of C118P and its active metabolite C118. Here, we first confirmed by in vitro assays that C118 exerts microtubule depolymerization activity and by molecular docking revealed that it fits to the colchicine binding site of tubulin. In addition, we found that C118P and C118 altered microtubule dynamics and cytoskeleton in human umbilical vein endothelial cells. Accordingly, we observed that C118P and C118 inhibited angiogenesis and disrupted established vascular networks using tube formation assays and chick chorioallantoic membrane angiogenesis assays. In addition, our data showed that C118P and C118 exhibited board anti-proliferative effect on various cancer cells, including HCC cell lines, in MTT assays or Sulforhodamine B assays. Moreover, we found that C118P induced G2/M phase cell cycle arrest and apoptosis in HCC cell lines BEL7402 and SMMC7721 using flow cytometry analysis and immunoblotting assays. Finally, we confirmed that C118P suppressed HCC growth via targeting tumor vasculature and inducing apoptosis in the SMMC7721 xenograft mouse model. In conclusion, our studies revealed that C118P, as a potent microtubule destabilizing agent, exerts its multiple pharmacological effects against HCC by inducing cell cycle arrest and apoptosis, as well as targeting tumor vasculature. Thus, C118P might be a promising drug candidate for liver cancer treatment.

Keywords: Anti-angiogenesis; C118P; Hepatocellular carcinoma; Microtubule; Vascular disrupting effect.