Transport and killing mechanism of a novel camptothecin-deoxycholic acid derivate on hepatocellular carcinoma cells. (July 2014)

• Record Type: Journal Article
• Authors: Li, Qingyong; Liu, Tianyu; Li, Yunchao; Luo, Shuyue; Zhu, Qiaochu; Zhang, Li; Zhao, Tengfei
• Is Part Of: Journal of drug targeting. Volume 22:Number 6(2014)
• Page Start: 543
• Page End: 552
• Publication Date: 2014-07
• Subjects: Drug delivery systems -- Periodicals; Drug Delivery Systems; Vehicles; Drug Administration Routes; Drug Evaluation; 615.7
• DOI: 10.3109/1061186X.2014.906603
• Languages: English
• ISSNs: 1061-186X

Abstract

<abstract> <title>Abstract</title> <p>Camptothecin-20(s)-<italic>O</italic>-glycine ester-[<italic>N</italic>-(3′α, 12′α-dihydroxy-24′-carbonyl-5′β-cholan)] (<bold>A2</bold>), 10-(3′α, 12′α-dihydroxy-5′β-cholan-24′-carboxyl)-(20 s)-camptothecin (<bold>C2</bold>), and 10-<italic>O</italic>-(3-<italic>O</italic>-(3′α, 12′α-dihydroxy-24′-carbonyl-5′β-cholan)-propyl)-(20<italic>S</italic>)-camptothecin (<bold>D2</bold>) are novel camptothecin-deoxycholic acid analogues. MTT assays were performed to assess the anticancer activity of these compounds against hepatocellular carcinoma SMMC-7721, breast carcinoma MCF-7, and colorectal carcinoma HCT-116 cells. <bold>A2</bold> had a high killing ability on SMMC-7721 cells selectively, but <bold>C2</bold> and <bold>D2</bold> did not exhibit selectivity with regard to SMMC-7721 killing. Uptake assays were performed in an effort to elucidate the transport mechanisms of <bold>A2</bold> into SMMC-7721 cells. <bold>A2</bold> increased the mRNA expression of OATP1B3 (an organic anion-transporting polypeptide) and uptake of <bold>A2</bold> was inhibited by rifampin (inhibitor of OATP1B3), which indicated that the transporter-mediated transport of <bold>A2</bold> was mediated by OATP1B3. In addition, according to the western blot and apoptosis assays, we found that A2 killed SMMC-7721 cells by inducing cell apoptosis mainly via an AIF (apoptosis-inducing factor) pathway and a caspase-dependent mitochondria apoptosis pathway.</p> </abstract>