Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model
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Chulwon Kim1, Jong Hyun Lee1, Sung-Hoon Kim1, Gautam Sethi2, Kwang Seok Ahn1
1College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea
2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
Gautam Sethi, e-mail: [email protected]
Kwang Seok Ahn, e-mail: [email protected]
Keywords: Artesunate, STAT5, CREB, MAPK, CML
Received: November 16, 2014 Accepted: December 21, 2014 Published: February 11, 2015
Artesunate (ART), a semi-synthetic derivative of artemisinin, is one of the most commonly used anti-malarial drugs. Also, ART possesses anticancer potential albeit through incompletely understood molecular mechanism(s). Here, the effect of ART on various protein kinases, associated gene products, cellular response, and apoptosis was investigated. The in vivo effect of ART on the growth of human CML xenograft tumors in athymic nu/nu mice was also examined. In our preliminary experiments, we first observed that phosphorylation of p38, ERK, CREB, Chk-2, STAT5, and RSK proteins were suppressed upon ART exposure. Interestingly, ART induced the expression of SOCS-1 protein and depletion of SOCS-1 using siRNA abrogated the STAT5 inhibitory effect of the drug. Also various dephosphorylations caused by ART led to the suppression of various survival gene products and induced apoptosis through caspase-3 activation. Moreover, ART also substantially potentiated the apoptosis induced by chemotherapeutic agents. Finally, when administered intraperitoneally, ART inhibited p38, ERK, STAT5, and CREB activation in tumor tissues and the growth of human CML xenograft tumors in mice without exhibiting any significant adverse effects. Overall, our results suggest that ART exerts its anti-proliferative and pro-apoptotic effects through suppression of multiple signaling cascades in CML both in vitro and in vivo.
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