Matrine inhibits BCR/ABL mediated ERK/MAPK pathway in human leukemia cells

// Lingdi Ma 1, * , Zhenyu Xu 2, * , Jian Wang 1 , Zhichao Zhu 3 , Guibin Lin 1 , Lijia Jiang 3 , Xuzhang Lu 4 and Chang Zou 5 1 Laboratory Center, The Third People’s Hospital of Huizhou, Affiliated Hospital of Guangzhou Medical University, Huizhou 516002, China 2 Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu 241001, China 3 Laboratory Center, The Second People’s Hospital of Changzhou, Affiliated Hospital of Nanjing Medical University, Changzhou 213000, China 4 Department of Hematology, The Second People’s Hospital of Changzhou, Affiliated Hospital of Nanjing Medical University, Changzhou 213000, China 5 Clinical Medical Research Center, The Second Clinical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China * These authors have contributed equally to this work Correspondence to: Lingdi Ma, email: lingdimawsh@126.com Keywords: matrine; ERK/MAPK; BCR/ABL; chronic myelogenous leukemia (CML); K562 cells Received: August 20, 2016     Accepted: June 30, 2017     Published: November 10, 2017 ABSTRACT The BCR/ABL fusion gene and its downstream signaling pathways such as Ras/Raf/MAPK, JAK/STAT3, and PI3K/AKT pathways play important roles in malignant transformation of leukemia, especially chronic myelogenous leukemia (CML). Our previous study showed that matrine, an alkaloid extracted from a Chinese herb radix sophorae, significantly inhibited the proliferation of human CML K562cells, induced cell cycle arrest in G0/G1, and promoted cell apoptosis. In the present study, we investigated the molecular mechanism of matrine in the growth inhibition of leukemia cells using K562 and HL-60 cell lines. RT-PCR and Western blot assay demonstrated that the expression of BCR/ABL in K562 and HL-60 cells was significantly inhibited by matrine treatment. Phosphorylation of MEK1, ERK1/2, and their upstream adaptor molecules Shc and SHP2 were significantly downregulated. The protein and mRNA expression of components of the ERK/MAPK signal pathway, and Bcl-xL, Cyclin D1, and c-Myc, were dramatically reduced. Conversely, the expression of p27, a negative regulator of cell cycle progression, increased after matrine treatment. These results indicated that the inhibition of ERK/MAPK and BCR/ABL signaling pathway was associated with matrine’s suppressive effects on the growth of K562 and HL-60 cells. In in vivo study, matrine significantly decreased the mortality rate of tumor-baring mice and suggested that matrine could exert its anti-leukemia effect in vivo.