Selective targeting of glioma-initiating cells by Eckol, a natural phlorotannin

Abstract

A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contributes to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to overcome resistance to anticancer treatments in human cancers. In this study, we show that Eckol, a phlorotannin compound, suppresses maintenance of glioma stem-like cell populations, and that Eckol in combination with anticancer treatments synergistically induces cell death of glioma stem-like cells. Treatment of neurosphere-forming glioma stem-like cells with Eckol effectively inhibited the neurosphere formation as well as the CD133+ cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers CD133, Nestin, and Musashi-1, and the known self-renewal-related proteins Sox2, Notch2, β-catenin in neurosphere-forming cells. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth and tumor formation of glioma stem-like cells. Importantly, treatment with Eckol effectively reduced the resistance of neurosphere-forming glioma stem-like cells to ionizing radiation and temozolomide. Interestingly, treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. Furthermore, in glioma stem-like cells derived from glioma patients, Eckol treatment effectively reduced stemness, and decreased resistance to anticancer treatments. These results indicate that the natural phlorotannin Eckol targets glioma stem-like cells, and synergistically enhances the sensitivity of glioma stem-like cells to anticancer treatments, suggesting that Eckol treatment may be beneficial in treating brain cancer by suppressing or eliminating brain cancer stem-like cells.