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Carcinogenesis Advance Access published online on June 15, 2005
Carcinogenesis, doi:10.1093/carcin/bgi157
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received April 12, 2005
Revised May 26, 2005
Accepted June 7, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway

Mohammad Saleem 1, Satwinderjeet Kaur 1, Mee-Hyang Kweon 1, Vaqar Mustafa Adhami 1, Farrukh Afaq 1, and Hasan Mukhtar 1*

1 Department of Dermatology, University of Wisconsin, Madison, WI, USA

* To whom correspondence should be addressed.
Hasan Mukhtar, E-mail: hmukhtar{at}wisc.edu


  Abstract

Pancreatic cancer is an exceptionally aggressive disease, the treatment of which has largely been unsuccessful due to higher resistance offered by pancreatic cancer cells to conventional approaches such as surgery, radiation and/or chemotherapy. The aberration of Ras oncoprotein has been linked to the induction of multiple signaling pathways and to the resistance offered by pancreatic cancer cells to the apoptosis. Therefore, there is a need for development of new and effective chemotherapeutic agents which can target multiple pathways to induce responsiveness of pancreatic cancer cells to death signals. In this study, human pancreatic adenocarcinoma cells AsPC-1 were used to investigate the effect of Lupeol on cell growth and its effects on the modulation of multiple Ras-induced signaling pathways. Lupeol caused a dose-dependent inhibition of cell growth as assessed by MTT assay and induction of apoptosis as assessed by flow cytometry, fluorescence microscopy and western blotting. Lupeol treatment to cells was found to significantly reduce the expression of Ras oncoprotein and modulate the protein expression of various signaling molecules involved in PKC{alpha}/ODC, PI3K/Akt and MAPKs pathways along with a significant reduction in the activation of NF{kappa}B signaling pathway. Our data suggests that Lupeol can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of pancreatic cancer cells. Lupeol could be a potential agent against pancreatic cancer however, further in-depth in vivo studies are warranted.

Keywords: Lupeol; Ras; ODC; PKC{alpha}; NF{kappa}B; Pancreatic cancer; chemoprevention.
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