Artesunate induces ROS- and p38 MAPK-mediated apoptosis and counteracts tumor growth in vivo in embryonal rhabdomyosarcoma cells
Artesunate induces ROS- and p38 MAPK-mediated apoptosis and counteracts tumor growth in vivo in embryonal rhabdomyosarcoma cells
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DOI：
10.1093/carcin/bgv098
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发表时间：
2015-09-01
期刊：
影响因子：
4.7
通讯作者：
Sorci, Guglielmo
中科院分区：
文献类型：
--
作者：
Beccafico, Sara;Morozzi, Giulio;Sorci, Guglielmo
横纹肌肉瘤约占儿童软组织肉瘤的50%和恶性实体瘤的10%。胚胎性横纹肌肉瘤（ERMS）是最常见的亚型，表明起源于肌肉前体细胞，其未能退出细胞周期并主要由于转录因子PAX 7的过表达而最终分化，PAX 7维持ERMS细胞的增殖、迁移和侵袭。青蒿琥酯（ARS）是青蒿素（ART）的半合成衍生物，青蒿素是一种天然化合物，是众所周知的抗疟疾药物。然而，已经发现ART及其衍生物甚至作为在几种癌症中诱导细胞周期停滞和/或细胞凋亡的抗癌药物是有效的。在这里，我们发现ARS剂量依赖性地诱导ERMS细胞系的DNA损伤和凋亡。活性氧（ROS）的产生和p38 MAPK的激活在触发ARS介导的ERMS细胞凋亡中起着核心作用;事实上，抗氧化剂N-乙酰半胱氨酸或p38 MAPK抑制剂SB 203580可以保护ERMS细胞免受ARS诱导的凋亡。此外，ARS处理ERMS细胞ROS依赖性诱导myo-miR、miR-133 a和miR-206的表达，其在RMS中下调，并降低PAX 7蛋白水平。最后，ARS上调粘附分子、NCAM和整联蛋白β 1的表达，并减少体外ERMS细胞的迁移和侵袭性，ARS治疗使体内ERMS异种移植物的生长减少约50%。我们的研究结果是第一个证据的疗效ART衍生物在抑制ERMS生长在体内，并建议ARS作为一个潜在的候选治疗ERMS。
Rhabdomyosarcoma represents about 50% of soft-tissue sarcomas and 10% of malignant solid tumors in childhood. Embryonal rhabdomyosarcoma (ERMS) is the most frequent subtype, suggested to have an origin in muscle precursor cells that fail to exit the cell cycle and terminally differentiate mainly because of overexpression of the transcription factor, PAX7, which sustains proliferation, migration and invasiveness in ERMS cells. Artesunate (ARS) is a semi-synthetic derivative of artemisinin (ART), a natural compound well known as an antimalarial drug. However, ART and its derivatives have been found efficacious even as anticancer drugs that induce cell cycle arrest and/or apoptosis in several kinds of cancer. Here, we show that ARS dose-dependently induces DNA damage and apoptosis in ERMS cell lines. Production of reactive oxygen species (ROS) and activation of p38 MAPK have a central role in triggering ARS-mediated apoptosis in ERMS cells; indeed either the antioxidant, N-acetylcysteine or the p38 MAPK inhibitor, SB203580, protects ERMS cells from ARS-induced apoptosis. Moreover, ARS treatment in ERMS cells ROS-dependently induces the expression of the myo-miRs, miR-133a and miR-206, which are down-regulated in RMS, and reduces PAX7 protein levels. Finally, ARS upregulates the expression of the adhesion molecules, NCAM and integrin beta 1, and reduces migration and invasiveness of ERMS cells in vitro, and ARS treatment reduces of about 50% the growth of ERMS xenografts in vivo. Our results are the first evidence of efficacy of ART derivatives in restraining ERMS growth in vivo, and suggest ARS as a potential candidate for therapeutic treatment of ERMS.