Suppressive effect of alpha-mangostin for cancer stem cells in colorectal cancer via the Notch pathway

Abstract

Background: Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. alpha-mangostin (alpha M) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of alpha M on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs. Methods: The cell viability assay was performed to determine the optimal concentration of alpha M. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the alpha M-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of alpha M on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of alpha M in combination with 5-FU was investigated using a xenograft mouse model. Results: alpha M inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. alpha M treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. alpha M markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, alpha M attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the alpha M group and in the alpha M group with 5-FU treatment. Conclusion: This study shows that low-dose alpha M inhibits CSCs in CRC and suppresses 5-FU-induced augmentation of CSCs via the Notch signaling pathway.