Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells

// Yao Yao 1, 2, 4, * , Yueyue Sun 1, 2, 4, * , Min Shi 1, 2, 4, * , Dandan Xia 1, 2, 4 , Kai Zhao 1, 2, 4 , Lingyu Zeng 1, 2, 4 , Ruosi Yao 1, 2, 4 , Ying Zhang 3 , Zhenyu Li 2 , Mingshan Niu 1, 2, 4 , Kailin Xu 1, 2, 4 1 Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China 2 Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China 3 Laboratory of Pathology, Xuzhou Medical College, Xuzhou, Jiangsu, China 4 Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China * These authors have contributed equally to this work Correspondence to: Kailin Xu, email: lihmd@163.com , kailinxu_xzmc@126.com Mingshan Niu, email: msniu24@126.com Keywords: multiple myeloma, STAT3, piperlongumine, bortezomib resistance, immunoproteasome Received: September 17, 2015     Accepted: September 02, 2016     Published: September 13, 2016 ABSTRACT Effective new therapies are urgently needed for the treatment of multiple myeloma (MM), an incurable hematological malignancy. In this study, we evaluated the effects of piperlongumine on MM cell proliferation both in vivo and in vitro . Piperlongumine inhibited the proliferation of MM cells by inducing cell apoptosis and blocking osteoclastogenesis. Notably, piperlongumine also reduced bortezomib resistance in MM cells. In a disseminated MM mouse model, piperlongumine prolonged the survival of tumor-bearing mice without causing any obvious toxicity. Mechanistically, piperlongumine inhibited the STAT3 signal pathway in MM cells by binding directly to the STAT3 Cys712 residue. These findings suggest that the clinical use of piperlongumine to overcome bortezomib resistance in MM should be evaluated.