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

Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
Ming LiuJing Li

Abstract

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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Citations

Jan 19, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Yongchun SongYu Yao
Feb 25, 2018·Naunyn-Schmiedeberg's Archives of Pharmacology·Sai Kiran S S PindiproluPavan Kumar Chintamaneni
Aug 23, 2017·Artificial Cells, Nanomedicine, and Biotechnology·Sai Kiran S S PindiproluVeera Venkata Satyanarayana Reddy Karri
Dec 4, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiaobin ZengNianhong Chen

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