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.
Highlights
IntroductionChemotherapy, irradiation, and hormone therapy are the major therapeutic options
Breast cancer is a common malignant tumor in woman
We previously showed that Sonic hedgehog (Shh) signaling pathway activation is associated with resistance to chemoradiation in esophageal adenocarcinoma [9] and resistance to multiple structurally unrelated chemotherapeutic agents through regulating MDR1 and BCRP expression [10]
Summary
Chemotherapy, irradiation, and hormone therapy are the major therapeutic options. Targeted therapy, such as Trastuzumab and lapatinib to inhibit the activity of receptors HER2/neu and epidermal-derived growth factor receptor (EGFR1), respectively, has already become clinically established as an effective and less toxic strategy for the treatment of breast cancer [1,2]. Multidrug resistance (MDR) is an unfavorable factor causing the failure of treatments against cancer cells [4]. It occurs when cancer cells acquire simultaneous resistance to various kinds of chemotherapeutic agents with no structural or functional similarities [5]. One of the mechanisms involved in MDR that reduces intracellular drug accumulation is the active efflux of chemotherapeutic agents through membrane drug transporters, especially the ATP-binding cassette (ABC) proteins, including p-glycoprotein (Pgp, MDR1, ABCB1), the multidrug resistance protein 1 (MRP1), and the breast cancer resistance protein (BCRP, ABCG2) [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
