In Vitro and In Vivo Anticancer Activity of Gimatecan against Hepatocellular Carcinoma

Abstract

<br /> <strong><span style="font-size: small;">Objective: </span></strong><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">Gimatecan is a new camptothecin (CPT) analogue that inhibits tumor growth by targeting DNA topoisomerase I (TOP I) and introducing strong and persistent DNA cleavage. Anti-tumor activity has been demonstrated with a wide range of solid tumors in previous preclinical and clinical studies. Here, we investigated for the first time the effects of gimatecan on the proliferation of hepatocellular carcinoma (HCC) cells both i</span></span><em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">n vitro </span></span></em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">and </span></span><em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">in vivo</span></span></em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">. </span></span><strong><span style="font-size: small;">Methods: </span></strong><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">Anticancer efficacy of gimatecan were evaluated in a panel of HCC cell lines and corresponding mouse xenograft models. Inhibition of cell proliferation was measured by CellTiter-Glo cell viability assay. </span></span><em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">In vivo</span></span></em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">, gimatecan and control preparations were orally administered every four days, for a total of four times. Tumor volume and body weights of the mice were measured twice weekly. </span></span><strong><span style="font-size: small;">Results: </span></strong><em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">In vitro </span></span></em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">cytotoxicity evaluation showed that gimatecan inhibited the proliferation of a large panel of HCC cell lines in a dose dependent manner, with IC50 values ranging between </span></span><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">12.1~1085.0 nM. </span></span><em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">In vivo </span></span></em><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">evaluation in mouse xenograft models showed significant antitumor effects of gimatecan at 0.8mg/kg and 0.4mg/kg as compared to the control group. </span></span><strong><span style="font-size: small;">Conclusion: </span></strong><span style="font-family: Times New Roman,Times New Roman; font-size: small;"><span style="font-family: Times New Roman,Times New Roman; font-size: small;">This study suggested that gimatecan may have the potential to be used as a chemotherapeutic agent for the treatment of HCC. </span></span>