title: Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin.
abstract: Cinobufagin (CBF) is isolated from the skin and posterior auricular glands of the Asiatic toad (Bufo gargarizans). This study investigated the reversal effect of CBF on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in colon cancer. The effect of CBF on the cytotoxicity of anticancer drugs in P-gp overexpressing LoVo/ADR, HCT116/L, Cao-2/ADR cells and their parental cells was determined using CCK-8 assay. Apoptosis of anti-cancer drugs and accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho123) in P-gp overexpressing cells were evaluated by flow cytometry. Results indicated that CBF significantly enhanced the sensitivity of P-gp substrate drugs on P-gp overexpressing cells, but had no effect on their parental cells. CBF enhanced the effect of DOX against P-gp-overexpressing LoVo/ADR cell xenografts in nude mice. Moreover, CBF also increased cell apoptosis of chemotherapy agents and intracellular accumulation of DOX and Rho123 in the MDR cells. Further research on the mechanisms revealed non-competitive inhibition of P-gp ATPase activity, but without altering the expression of P-gp. These findings demonstrated that CBF could be further developed into a safe and potent P-gp modulator for combination use with anticancer drugs in cancer chemotherapy.
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Zeting
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Shi
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pharmacy, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jia
authors.affiliation: Department of Pharmacy, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: He
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai 200062, P.R. China.
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002018:Bufanolides / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D002018:Bufanolides; D004317:Doxorubicin; C002471:cinobufagin