Artesunate induces ROS-mediated apoptosis and counteracts tumor growth in vivo in embryonal rhabdomyosarcoma cells.

Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue sarcoma in childhood, and is characterized by the expression of muscle-specific transcription factors and overexpression of PAX7 [1]. Thus, ERMS has been suggested to have an origin in muscle precursor cells that fail to exit the cell cycle and terminally differentiate. Artesunate (ARS) is a semi-synthetic derivate of artemisinin, a Chinese-medicine compound long known as a very effective anti-malarial drug. More recently, artemisinin and its derivatives have been found effective as anticancer drugs since they induce cell cycle arrest or apoptosis in several kinds of cancer [2]. Here we demonstrate that ARS dose-dependently induces cell cycle arrest and apoptosis in the ERMS cell lines, TE671 and RD18. Production of reactive oxygen species (ROS) and activation of p38 MAPK have a central role in triggering ARS-mediated apoptosis in ERMS cells, since either the antioxidant and ROS scavenger, N-acetylcysteine (NAC), or the p38 inhibitor, SB203580, protects ERMS cells from ARS-induced apoptosis. Moreover, ARS treatment in ERMS cells ROS-dependently induces the expression of the specific myo-miRs, miR-133a and miR-206, which are typically down-regulated in ERMS, and downregulates PAX7 expression. Finally, ARS upregulates the expression of the adhesion molecules, NCAM and integrin 1, and reduces migration and invasiveness in ERMS cells in vitro, and ARS treatment reduces ERMS tumor growth in vivo. Our results suggest ARS as a potential candidate for the therapeutic treatment of ERMS. 1. Parham D.M. and Ellison D.A. (2006) Rhabdomyosarcomas in adults and children. An update. Arch. Pathol. Lab. Med. 130:1454-1465 2. Crespo-Ortiz M.P. and Wei M.Q. (2012) Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J. Biomed. Biotechnol. 2012:247597