https://scholars.lib.ntu.edu.tw/handle/123456789/564818
標題: | A unique P-glycoprotein interacting agent displays anticancer activity against hepatocellular carcinoma through inhibition of GRP78 and mTOR pathways | 作者: | Kuo T.-C. Chiang P.-C. Yu C.-C. Nakagawa-Goto K. Bastow K.F. Lee K.-H. JIH-HWA GUH |
關鍵字: | ATPase activity; GRP78; mTOR pathways; Multidrug resistance; P-glycoprotein | 公開日期: | 2011 | 卷: | 81 | 期: | 9 | 起(迄)頁: | 1136-1144 | 來源出版物: | Biochemical Pharmacology | 摘要: | P-glycoprotein (P-gp) overexpression has been demonstrated in many malignancies being a predominant mechanism by which cancer cells develop multidrug resistance. Several categories of P-gp inhibitors have been demonstrated to potentiate anticancer effect induced by cancer chemotherapeutic drugs through competitive inhibition of P-gp pumping activity. Few studies show the agent that selectively acts on P-gp and, by itself, causes cell apoptosis while remain P-gp-deficient cells unaffected. KNG-I-322, a desmosdumotin B derivative, displayed a direct interaction with P-gp and demonstrated selective anti-proliferative and apoptotic activities in P-gp overexpressed Hep3B/VIN other than P-gp-deficient Hep3B cells. KNG-I-322 induced an inhibitory effect on the phosphorylation of mTORSer2448, p70S6KThr389 and 4E-BPThr37/46 in Hep3B/VIN but not Hep3B cells. The inhibition was fully blocked by the knockdown of P-gp using siRNA techniques. Notably, the P-gp inhibitor, verapamil, also directly interacted with P-gp but significantly diminished KNG-I-322-induced anti-proliferative activity. After the mechanism study, the data showed that KNG-I-322 induced a dramatic down-regulation of GRP78 expression, which was significantly inhibited by verapamil and completely diminished by the knockdown of P-gp. The protein profile analysis of detergent resistant membranes showed that upon the stimulation by KNG-I-322, the level of P-gp expression in non-raft fractions was dramatically increased and, concomitantly, the GRP78 expression was significantly decreased. Taken together, the data suggest that KNG-I-322 induces anticancer activity in Hep3B/VIN cells through a direct interaction with P-gp, leading to the inhibition of mTOR pathways and the induction of GRP78 down-regulation. The data support that KNG-I-322 is a selective anticancer agent against P-gp-overexpressed other than P-gp-deficient cancer cells. ? 2011 Elsevier Inc. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-79953725972&doi=10.1016%2fj.bcp.2011.02.013&partnerID=40&md5=ea50f1690c19cb08cdd3f6dacf1d7d1a https://scholars.lib.ntu.edu.tw/handle/123456789/564818 |
ISSN: | 62952 | DOI: | 10.1016/j.bcp.2011.02.013 | SDG/關鍵字: | genistein; glucose regulated protein 78; glycoprotein P; glycoprotein P inhibitor; kng i 322; mammalian target of rapamycin; S6 kinase; small interfering RNA; unclassified drug; verapamil; antineoplastic activity; article; controlled study; drug antagonism; drug effect; drug mechanism; human; human cell; liver cell carcinoma; priority journal; protein expression; protein phosphorylation; Antineoplastic Agents; Base Sequence; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; DNA Primers; Drug Screening Assays, Antitumor; Flavones; Heat-Shock Proteins; Humans; Liver Neoplasms; P-Glycoprotein; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; TOR Serine-Threonine Kinases |
顯示於: | 藥學系 |
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