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Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells.
PLoS One. 2012; 7(5):e37006.Plos

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+Show Affiliations

Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22615870

Citation

Chen, Yu-Jen, et al. "Small-molecule Synthetic Compound Norcantharidin Reverses Multi-drug Resistance By Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells." PloS One, vol. 7, no. 5, 2012, pp. e37006.
Chen YJ, Kuo CD, Chen SH, et al. Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells. PLoS One. 2012;7(5):e37006.
Chen, Y. J., Kuo, C. D., Chen, S. H., Chen, W. J., Huang, W. C., Chao, K. S., & Liao, H. F. (2012). Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells. PloS One, 7(5), e37006. https://doi.org/10.1371/journal.pone.0037006
Chen YJ, et al. Small-molecule Synthetic Compound Norcantharidin Reverses Multi-drug Resistance By Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells. PLoS One. 2012;7(5):e37006. PubMed PMID: 22615870.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Small-molecule synthetic compound norcantharidin reverses multi-drug resistance by regulating Sonic hedgehog signaling in human breast cancer cells. AU - Chen,Yu-Jen, AU - Kuo,Cheng-Deng, AU - Chen,Szu-Han, AU - Chen,Wei-Jen, AU - Huang,Wen-Chien, AU - Chao,K S Clifford, AU - Liao,Hui-Fen, Y1 - 2012/05/15/ PY - 2011/10/19/received PY - 2012/04/11/accepted PY - 2012/5/23/entrez PY - 2012/5/23/pubmed PY - 2013/1/9/medline SP - e37006 EP - e37006 JF - PloS one JO - PLoS One VL - 7 IS - 5 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22615870/Small_molecule_synthetic_compound_norcantharidin_reverses_multi_drug_resistance_by_regulating_Sonic_hedgehog_signaling_in_human_breast_cancer_cells_ L2 - https://dx.plos.org/10.1371/journal.pone.0037006 DB - PRIME DP - Unbound Medicine ER -