title: Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.
abstract: Multi-drug resistance (MDR), an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC) transporters and activated Sonic hedgehog (Shh) signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX), we examined the effect and mechanism of norcantharidin (NCTD), a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S) and DOX-resistant (MCF-7R) cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.
authors.affiliation: Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Cheng-Deng
authors.initials: CD
authors.lastname: Kuo
authors.forename: Szu-Han
authors.initials: SH
authors.lastname: Chen
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Chen
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: K S Clifford
authors.initials: KS
authors.lastname: Chao
authors.forename: Hui-Fen
authors.initials: HF
authors.lastname: Liao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D053823:Hedgehog Proteins; D012333:RNA, Messenger; C509239:SHH protein, human; D014747:Vinblastine; D004317:Doxorubicin; C069741:norcantharidin; D000077235:Vinorelbine