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.

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.