Transport and killing mechanism of a novel camptothecin-deoxycholic acid derivate on hepatocellular carcinoma cells.
Abstract Camptothecin-20(s)-O-glycine ester-[N-(3'α, 12'α-dihydroxy-24'-carbonyl-5'β-cholan)] (A2), 10-(3'α,12'α-dihydroxy-5'β-cholan-24'-carboxyl)-(20 s)-camptothecin (C2), and 10-O-(3-O-(3'α, 12'α-dihydroxy-24'-carbonyl-5'β-cholan)-propyl)-(20S)-camptothecin (D2) 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. A2 had a high killing ability on SMMC-7721 cells selectively, but C2 and D2 did not exhibit selectivity with regard to SMMC-7721 killing. Uptake assays were performed in an effort to elucidate the transport mechanisms of A2 into SMMC-7721 cells. A2 increased the mRNA expression of OATP1B3 (an organic anion-transporting polypeptide) and uptake of A2 was inhibited by rifampin (inhibitor of OATP1B3), which indicated that the transporter-mediated transport of A2 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.
College of Pharmaceutical Science, Zhejiang University of Technology , Hangzhou , China .
Qingyong
Q
Li
Tianyu
T
Liu
Yunchao
Y
Li
Shuyue
S
Luo
Qiaochu
Q
Zhu
Li
L
Zhang
Tengfei
T
Zhao
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002166:Camptothecin / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D027361:Organic Anion Transporters / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D002166:Camptothecin
Apoptosis; camptothecin; deoxycholic acid; uptake