title: Beneficial effect of cepharanthine on overcoming drug-resistance of hepatocellular carcinoma.
abstract: Despite improvement in liver surgery, patient prognoses after surgical resection for hepatocellular carcinoma (HCC) remain unsatisfactory. One of the obstacles in managing post-operative recurrence is resistance to chemotherapy. We examined the effect of Cepharanthin (CEP), a natural alkaloid extracted from Stephania cepharantha Hayata, in overcoming P-glycoprotein (P-gp)-associated doxorubicine (DOX) resistance, using 2 DOX-resistant HCC cell lines, and their DOX-sensitive parental cell lines. P-gp expression in surgically removed HCC tumours was also examined. In the in vitro study, overexpression of P-gp in the resistant cells was confirmed by immunoblotting and RT-PCR. Drug sensitivity testing with MTT assay showed that co-administration of CEP significantly enhanced cytotoxicity of DOX, but only in resistant cells. Flow cytometric analysis revealed that CEP significantly increased intracellular DOX concentration by inhibiting DOX efflux. P-gp expression in 107 patients with HCC was examined retrospectively by immunohistochemistry. P-gp was overexpressed in the tumours of 36% of these patients, especially in well-differentiated tumours that are often insensitive to chemotherapy, supporting the use of P-gp modulation as a new chemotherapeutic approach. Multivariate logistic regression analysis revealed that serum alpha-fetoprotein level was inversely related to P-gp expression. Our data suggest that co-administration of CEP with DOX may potentiate the effect of chemotherapy on drug-resistant HCC.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. soul-provider@mua.biglobe.ne.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Nakajima
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Koichiro
authors.initials: K
authors.lastname: Hata
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.forename: Kei
authors.initials: K
authors.lastname: Yonezawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000368:Aged; D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D044182:Benzylisoquinolines; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D052117:Benzodioxoles
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D004396:Coloring Agents; D004317:Doxorubicin; D013778:Tetrazolium Salts; D013844:Thiazoles; C006947:cepharanthine; D052117:Benzodioxoles; C022616:thiazolyl blue