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Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent

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Tumor Biology

Abstract

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer that arises from the skeletal muscle. Recent studies have identified an important role of AKT signaling in RMS progression. In the current study, we investigated the activity of perifosine, an oral alkylphospholipid AKT inhibitor, against human RMS cells (RD and Rh-30 lines) both in vivo and in vitro, and studied the underlying mechanisms. We showed that perifosine significantly inhibited RMS cell growth in concentration- and time-dependent manners. Meanwhile, perifosine induced dramatic apoptosis in RMS cells. At the signaling level, perifosine blocked AKT activation, while inducing reactive oxygen species (ROS) production as well as JNK and P38 phosphorylations in RMS cells. Restoring AKT activation by introducing a constitutively active-AKT (CA-AKT) only alleviated (not abolished) perifosine-induced cytotoxicity in RD cells. Yet, the ROS scavenger N-acetyl cysteine (NAC) as well as pharmacological inhibitors against JNK (SP-600125) or P38 (SB-203580) suppressed perifosine-induced cytotoxicity in RMS cells. Thus, perifosine induces growth inhibition and apoptosis in RMS cells through mechanisms more than just blocking AKT. In vivo, oral administration of perifosine significantly inhibited growth of Rh-30 xenografts in severe combined immunodeficient (SCID) mice. Our data indicate that perifosine might be further investigated as a promising anti-RMS agent.

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Acknowledgments

This work is supported by the Project of Science and Technology Department of Zhejiang Province (2014C33206).

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Authors and Affiliations

  1. Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, No. 79 Qing-chun Road, Hangzhou, Zhejiang, 310003, People’s Republic of China

    Jie Shen, Yue Hong & Jian-li Zhang

  2. Department of Thoracic Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, 310003, People’s Republic of China

    Qiong Zhao

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  1. Jie Shen
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  2. Yue Hong
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  3. Qiong Zhao
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  4. Jian-li Zhang
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Correspondence to Qiong Zhao or Jian-li Zhang.

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Shen, J., Hong, Y., Zhao, Q. et al. Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent. Tumor Biol. 37, 1025–1033 (2016). https://doi.org/10.1007/s13277-015-3740-4

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  • DOI: https://doi.org/10.1007/s13277-015-3740-4

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