Beneficial effect of cepharanthine on overcoming drug-resistance of hepatocellular carcinoma.

Akio Nakajima, Yuzo Yamamoto, Kojiro Taura, Koichiro Hata, Manabu Fukumoto, Hiroshi Uchinami, Kei Yonezawa, Yoshio Yamaoka

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34 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)635-645
Number of pages11
JournalInternational journal of oncology
Issue number3
Publication statusPublished - 2004 Mar

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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