Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma

// Yun Wang 1, * , Nanxin Huang 1, * , Hongli Li 1 , Shubao Liu 1 , Xianjun Chen 1 , Shichang Yu 2 , Nan Wu 3 , Xiu-Wu Bian 2 , Hai-Ying Shen 4, * , Chengren Li 1 and Lan Xiao 1, * 1 Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China 2 Department of Pathology, Southwest Hospital, Chongqing 400038, China 3 Department of Neurosurgery, Southwest Hospital, Chongqing 400038, China 4 Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA * These authors have contributed equally to this work Correspondence to: Chengren Li, email: lichengren@sohu.com Lan Xiao, email: xiaolan35@hotmail.com Keywords: quetiapine, glioma stem cell, proliferation, differentiation, Wnt/β-catenin signaling pathway Received: November 02, 2016     Accepted: March 01, 2017     Published: March 21, 2017 ABSTRACT As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.