Isocyclopamine, a novel synthetic derivative of cyclopamine, reverts doxorubicin resistance in MCF-7/ADR cells by increasing intracellular doxorubicin accumulation and downregulating breast cancer stem-like cells
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Cyclopamine (CPM) showed promise as a human cancer chemotherapy agent. However, limitations such as stomach acid instability and low solubility impair its clinical application. In this study, we synthesized a novel CPM analogue, isocyclopamine (ICPM), which had comparative bioactivity with CPM and improved stability and solubility. ICPM reversed doxorubicin resistance and had potent synergy with doxorubicin in MCF-7/ADR cells. We further demonstrated that the synergistic mechanism was related to the increased intracellular accumulation of doxorubicin in the cells and the downregulation of the cancer stem-like cells via modulation on both ABCB1 and ABCG2 transporters with independence of Smoothened. The present study identified ICPM as a novel derivative of CPM with better stability and solubility, which provided a useful tool for the biological and medicinal studies, as well as a novel agent for the development of new cancer chemotherapy with improved efficacy.
KeywordsCyclopamine Isocyclopamine MCF-7/ADR ABCB1 ABCG2
This work was supported by NSFC-Shandong Joint Fund (No. U1406402), the Natural Science Foundation of China (No. 81373323), the Natural Science Foundation of Shandong Province (No. ZR2012CM005, No. ZR2015HM010), and the Young Talent Project at Ocean University of China (No. 201412007).
Conflict of interest
- 3.Legrand O, Simonin G, Beauchamp-Nicoud A, Zittoun R, Marie J-P. Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia, vol. 3. 1999.Google Scholar
- 9.Sims-Mourtada J, Izzo JG, Ajani J, Chao KSC. Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene. 2007;26(38):5674–9. http://www.nature.com/onc/journal/v26/n38/suppinfo/1210356s1.html.CrossRefPubMedGoogle Scholar
- 16.Wang M, Wang Y, Zhong J. Side population cells and drug resistance in breast cancer. Mol Med Rep. 2015;30:10.Google Scholar
- 22.Yu L, Wu WKK, Li ZJ, Liu QC, Li HT, Wu YC, et al. Enhancement of doxorubicin cytotoxicity on human esophageal squamous cell carcinoma cells by indomethacin and 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC236) via inhibiting P-Glycoprotein activity. Mol Pharmacol. 2009;75(6):1364–73. doi: 10.1124/mol.108.053546.CrossRefPubMedGoogle Scholar
- 26.Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 2000;406(6799):1005–9. http://www.nature.com/nature/journal/v406/n6799/suppinfo/4061005a0_S1.html.CrossRefPubMedGoogle Scholar