Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent
- 137 Downloads
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.
KeywordsRhabdomyosarcoma (RMS) AKT Perifosine Signaling and apoptosis
This work is supported by the Project of Science and Technology Department of Zhejiang Province (2014C33206).
Conflicts of interest
- 3.Spunt SL, Smith LM, Ruymann FB, Qualman SJ, Donaldson SS, Rodeberg DA, et al. Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the soft tissue sarcoma committee of the children’s oncology group. Clin Cancer Res. 2004;10:6072–9.CrossRefPubMedGoogle Scholar
- 8.Cao L, Yu Y, Darko I, Currier D, Mayeenuddin LH, Wan X, et al. Addiction to elevated insulin-like growth factor i receptor and initial modulation of the akt pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody. Cancer Res. 2008;68:8039–48.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, et al. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010;9:963–75.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Rahmani M, Reese E, Dai Y, Bauer C, Payne SG, Dent P, et al. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through akt and erk1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Res. 2005;65:2422–32.CrossRefPubMedGoogle Scholar
- 33.Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R, et al. Clinical and translational studies of a phase ii trial of the novel oral akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2010;16:1033–41.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Knowling M, Blackstein M, Tozer R, Bramwell V, Dancey J, Dore N, et al. A phase ii study of perifosine (d-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: a National Cancer Institute Of Canada Clinical Trials Group trial. Investig New Drugs. 2006;24:435–9.CrossRefGoogle Scholar