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

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

BECCAFICO, SARA;SIDONI, Angelo;DONATO, Rosario Francesco;SORCI, Guglielmo
2014

Abstract

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
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1318905
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact