Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 4, pp 711–719 | Cite as

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

  • Ying Xin
  • Xiang-di Shen
  • Long ChengEmail author
  • De-fei Hong
  • Bin ChenEmail author
Original Article



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


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.


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.


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


The pancreatic cancer Perifosine Gemcitabine Akt–mTOR Hh–Gli signaling 



Glioma-associated oncogenes


Mammalian target of rapamycin


Mitogen-activated protein kinase




Cell counting kit-8




Suppressor of fused


Patched 1



This work was supported by the talent plan of Science and Technology Bureau of Zhejiang Province (2012R10043). The founders have no roles in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Conflict of interest

No conflict of interests are stated.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Thyroid and Breast SurgeryZhejiang Provincial People’s HospitalHangzhouChina
  2. 2.Office of ResearchZhejiang Medical CollegeHangzhouChina
  3. 3.Department of Interventional RadiologyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
  4. 4.Department of Hepatobiliary SurgeryZhejiang Provincial People’s HospitalHangzhouChina
  5. 5.Department of General SurgeryNo.1 People’s Hospital of HangzhouHangzhouChina

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