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Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent
Jie Shen1, Yue Hong1, Qiong Zhao2
1Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, No. 79 Qing-chun Road, Hangzhou, Zhejiang, 310003, People's Republic of China.
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.
Insights
Perifosine, an AKT inhibitor, effectively reduces rhabdomyosarcoma (RMS) growth and induces apoptosis in preclinical models. Its anti-cancer effects involve mechanisms beyond AKT inhibition, including ROS production and JNK/P38 activation.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Rhabdomyosarcoma (RMS) is a pediatric skeletal muscle cancer with high metastatic potential.
- AKT signaling pathways are implicated in RMS progression and therapeutic resistance.
Purpose of the Study:
- To investigate the efficacy of perifosine, an oral AKT inhibitor, against human RMS cells in vitro and in vivo.
- To elucidate the underlying molecular mechanisms of perifosine's anti-RMS activity.
Main Methods:
- In vitro studies using RD and Rh-30 RMS cell lines treated with perifosine.
- In vivo studies involving perifosine administration to Rh-30 xenografts in SCID mice.
- Analysis of signaling pathways including AKT, ROS, JNK, and P38 phosphorylation.
Main Results:
- Perifosine significantly inhibited RMS cell growth and induced apoptosis in a dose- and time-dependent manner.
- Perifosine blocked AKT activation, increased reactive oxygen species (ROS) production, and activated JNK and P38 pathways.
- Inhibition of ROS, JNK, or P38 pathways partially reversed perifosine-induced cytotoxicity.
- Perifosine administration significantly suppressed tumor growth in a xenograft mouse model.
Conclusions:
- Perifosine exhibits potent anti-rhabdomyosarcoma activity both in vitro and in vivo.
- The anti-cancer effects of perifosine are mediated through complex mechanisms involving AKT inhibition, ROS generation, and JNK/P38 activation.
- Perifosine represents a promising therapeutic agent for rhabdomyosarcoma treatment.
