Journal
TUMOR BIOLOGY
Volume 37, Issue 2, Pages 1919-1931Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1007/s13277-015-3997-7
Keywords
Cyclopamine; Isocyclopamine; MCF-7/ADR; ABCB1; ABCG2
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Funding
- NSFC-Shandong Joint Fund [U1406402]
- Natural Science Foundation of China [81373323]
- Natural Science Foundation of Shandong Province [ZR2012CM005, ZR2015HM010]
- Ocean University of China [201412007]
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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.
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