breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist乳腺癌干细胞样细胞是由无毒芳基碳氢化合物抑制受体激动剂.pdf

Breast Cancer Stem-Like Cells Are Inhibited by a Non- Toxic Aryl Hydrocarbon Receptor Agonist ´ 1,2 1,2 1,2 1,2 Gerald J. Prud’homme *, Yelena Glinka , Anna Toulina , Olga Ace , Venkateswaran Subramaniam1,2, Serge Jothy1,2 1 Department of Laboratory Medicine and Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Canada, 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada Abstract Background: Cancer stem cells (CSCs) have increased resistance to cancer chemotherapy. They can be enriched as drug- surviving CSCs (D-CSCs) by growth with chemotherapeutic drugs, and/or by sorting of cells expressing CSC markers such as aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors following xenotransplantation in Scid mice. We hypothesized that tranilast, a non-toxic orally active drug with anti-cancer activities, would inhibit breast CSCs. Methodology/Findings: We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formed mammospheres, at pharmacologically relevant concentrations. It was effective against D-CSCs of both HER-2+ and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice i