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Cancer Chemotherapy and Pharmacology

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01-04-2014 | Original Article

Perifosine inhibits S6K1–Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency

Authors: Ying Xin, Xiang-di Shen, Long Cheng, De-fei Hong, Bin Chen

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2014

Abstract

Purpose

The pancreatic cancer has extremely low overall 5-year survival, and gemcitabine is the only approved single agent for pancreatic cancer treatment.

Methods

In the present study, we investigated the potential effect of perifosine, a novel Akt inhibitor on gemcitabine-induced anti-pancreatic cancer effect both in vivo and in vitro.

Results

We showed that sub-cytotoxic low concentration of perifosine dramatically enhanced gemcitabine-induced cytotoxicity in cultured pancreatic cancer cells. Perifosine inhibited Akt–mammalian target of rapamycin and Erk–mitogen-activated protein kinase activation in pancreatic cancer cells. Meanwhile, perifosine suppressed the hedgehog signaling, as it inhibited glioma-associated oncogenes (Gli) 1 activation and decreased its target protein patched 1 (PTCH1) expression. Our data demonstrated that perifosine blocked p70S6K1 (S6K1) activation, thus disrupting S6K1–Gli1 association and subsequent Gli1 activation. The reduction of S6K1 or Gli1 expression by target siRNAs inhibited PTCH1 expression and enhanced gemcitabine-induced cytotoxicity in pancreatic cancer cells. Significantly, perifosine dramatically enhanced gemcitabine-mediated antitumor effect in a PANC-1 xenograft severe combined immunodeficiency mice model.

Conclusions

In summary, we conclude that perifosine sensitizes gemcitabine-mediated anti-pancreatic cancer efficiency through regulating multiple signaling pathways.

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Title: Perifosine inhibits S6K1–Gli1 signaling and enhances gemcitabine-induced anti-pancreatic cancer efficiency
Authors: Ying Xin
Xiang-di Shen
Long Cheng
De-fei Hong
Bin Chen
Publication date: 01-04-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2014
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2397-9

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Purpose

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