Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent.
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.
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
J
Shen
Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, No. 79 Qing-chun Road, Hangzhou, Zhejiang, 310003, People's Republic of China.
Yue
Y
Hong
Department of Thoracic Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, 310003, People's Republic of China. drzhang_qiong@163.com.
Qiong
Q
Zhao
Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, No. 79 Qing-chun Road, Hangzhou, Zhejiang, 310003, People's Republic of China. zjlhangzhoudr11@163.com.
Jian-Li
JL
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt
AKT; Perifosine; Rhabdomyosarcoma (RMS); Signaling and apoptosis