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Withaferin A targeting both cancer stem cells and metastatic cancer stem cells in the UP-LN1 carcinoma cell model Lai-Lei Ting1, Andy Shau-Bin Chou2, Chin-Hsuan Hsieh3, Shih-Chieh Hsiung3, See-Tong Pang3, Shuen-Kuei Liao4,5 1Department of Radiation Oncology, Cancer Center, Taipei Medical University Hospital, Taipei 110, Taiwan, China. 2Department of Radiology, Tzu-Chi General Hospital, Hualien 970, Taiwan, China. 3Department of Surgery, Division of Uro-Oncology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, China. 4The PhD Program of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan, China. 5Department of Research and Development, Vectorite Biomedica Inc., New Taipei City 221, Taiwan, China. Correspondence to: Dr. Shuen-Kuei Liao, The PhD Program of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan, China. E-mail: liaosk@h.tmu.edu.tw Aim: As our understanding of cancer stem cell (CSC) biology improves, search for inhibitory agents of CSCs and metastatic CSCs (mCSCs) positive for CXCR4 is warranted. Withaferin A (WA), a withanolide extracted from the medicinal plant Withania somnifera, has been shown to exhibit anti-cancer effects through multiple mechanisms. Whether WA could selectively target CSCs, mCSCs, or nonCSCs of a gastrointestinal (GI) carcinoma tumor remains unclear. Methods: Side-population (SP) analysis, flow cytometric phenotyping and sorting, non-invasive imaging in conjunction with xenotransplantation, and immunohistology were used in this investigation. Results: Using the lymph node metastatic GI cancer cell line UP-LN1, consisting of CD44high/CD24low floating (F) and CD44low/CD24high adherent (A) cell subsets, this study demonstrated that as compared with parental UP-LN1 cells or A cells, WA preferentially reduced F-cell proliferation, tumor sphere formation, and SP cells in vitro in greater effi ciencies by apoptosis. This action was mechanistically mediated via the down-regulation of CXCR4/CXCL12 and STAT3/interleukin-6 axes, both of which are instrumental in the acquisition of metastatic ability. Attenuation of interferon-γ-induced CXCR4 expression in F cells by knockdown with siRNA or blocking with an anti-CXCR4 antibody, followed by Western blot analysis, showed signifi cantly reduced metastatic potential in vitro. The extent of in vitro anti-invasive effect of WA on the IFN-γ-treated F cells was signifi cantly greater than on the F cells without WA treatment, or F cells treated with control siRNA or with control IgG antibody. The observed in vitro effects of WA on the CSC and mCSC targeting were validated by data obtained with non-invasive imaging in NOD/SCID mouse xenotransplantation. Conclusion: WA could effi ciently block the formation of both CSCs and mCSCs in the UP-LN1 cell line, suggesting that WA may be considered an effective therapeutic agent for this type of GI malignancies.