Antineoplastic effects of CPPTL via the ROS/JNK pathway in acute myeloid leukemia

// Hui-Er Gao 1, * , Yue Sun 1, * , Ya-Hui Ding 2 , Jing Long 2 , Xiao-Lei Liu 1 , Ming Yang 1 , Qing Ji 1 , Ying-Hui Li 1 , Yue Chen 2 , Quan Zhang 2 , Ying-Dai Gao 1 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China 2 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300353, P. R. China * These authors contributed equally to this work Correspondence to: Quan Zhang, email: zhangquan612@163.com Ying-Dai Gao, email: ydgao@ihcams.ac.cn Keywords: CPPTL, acute myeloid leukemia, ROS, JNK pathway Received: February 23, 2017      Accepted: April 03, 2017      Published: April 17, 2017 ABSTRACT Drug resistance and human leukocyte antigen (HLA) matching limit conventional treatment of acute myeloid leukemia (AML). Although several small molecule drugs are clinically used, single drug administration is not sufficient to cure AML, which has a high molecular diversity. Metabolic homeostasis plays a key role in determining cellular fate. Appropriate levels of reactive oxygen species (ROS) maintain the redox system balance, and excessive amounts of ROS cause oxidative damage, thus providing a strategy to eliminate cancer cells. CPPTL is a novel analogue of parthenolide that exhibited significant cytotoxicity to AML cells in vitro and induced apoptosis in a dose-dependent manner. Additionally, CPPTL’s prodrug DMA-CPPTL decreased the burden of AML engraftment and prolonged survival in a mouse model administered human primary AML cells in vivo . CPPTL induced apoptosis of AML cells by stimulating ROS production, and accumulation of ROS then activated the JNK pathway, thereby promoting mitochondrial damage. These results demonstrated that CPPTL effectively eradicated AML cells in vitro and in vivo and suggested that CPPTL may be a novel candidate for auxiliary AML therapy.