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Perifosine Induces Cell Apoptosis in Human Osteosarcoma Cells: New Implication for Osteosarcoma Therapy?

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Abstract

Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis for patients with osteosarcoma is generally poor. The search for more effective anti-osteosarcoma agents is necessary and urgent. Here we report that perifosine induces cell apoptosis and growth inhibition in cultured human osteosarcoma cells. Perifosine blocks Akt/mTOR complex 1 (mTORC1) signaling, while promoting caspase-3, c-Jun N-terminal kinases (JNK), and p53 activation. Further, perifosine inhibits survivin expression probably by disrupting its association with heat shock protein-90 (HSP-90). These signaling changes together were responsible for a marked increase of osteosarcoma cell apoptosis and growth inhibition. Finally, we found that a low dose of perifosine enhanced etoposide- or doxorubicin-induced anti-OS cells activity. The results together suggest that perifosine might be used as a novel and effective anti-osteosarcoma agent.

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Abbreviations

mTORC1:

mTOR complex 1

JNK:

c-Jun N-terminal kinases

ERK:

Extracellular signal-regulated kinase

MTT:

3-[4,5-dimethylthylthiazol-2-yl]-2,5 diphenyltetrazolium bromide

HSP-90:

Heat shock protein-90

PBS:

Phosphate-buffered saline

ROS:

Reactive oxygen species

HDACi:

Histone deacetylase inhibitor

PI3K:

Phosphoinositide 3-kinase

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Authors and Affiliations

  1. Department of Orthopedics, BenQ Medical Center, Nanjing Medical University, Nanjing, 210019, Jiangsu, China

    Chen Yao, Jian-jun Wei, Zu-yu Wang, Hui-min ding, Dong Li, Shi-chang Yan, Yong-jiang Yang & Zhang-ping Gu

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Correspondence to Zhang-ping Gu.

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Fig. S1

Perifosine inhibits Akt phosphorylation in cultured osteosarcoma cells. U2OS, SaOs-2 and MG-63 osteosarcoma cells were treated with indicated concentration of perifosine for 12 h, p-Akt (Ser 473) and Akt1 were examined by Western blot (EPS 814 kb)

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Yao, C., Wei, Jj., Wang, Zy. et al. Perifosine Induces Cell Apoptosis in Human Osteosarcoma Cells: New Implication for Osteosarcoma Therapy?. Cell Biochem Biophys 65, 217–227 (2013). https://doi.org/10.1007/s12013-012-9423-5

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