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Carcinogenesis Advance Access originally published online on August 27, 2007
Carcinogenesis 2007 28(11):2337-2346; doi:10.1093/carcin/bgm189
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

2-Cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor {gamma} in colon and pancreatic cancer cells

Sudhakar Chintharlapalli1,{dagger}, Sabitha Papineni1,{dagger}, Shengxi Liu1, Indira Jutooru2, Gayathri Chadalapaka2, Sung-dae Cho1, Rajesh S. Murthy3, Youngjae You3 and Stephen Safe1,2,*

1 Institute of Biosciences and Technology, Texas A&M University Health Science Center,Houston, TX 77030-3303, USA
2 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA
3 Department of Chemistry, South Dakota State University, Brookings, SD 57007, USA

* To whom correspondence should be addressed. Tel: +979 845 5988; Fax: +979 862 4929; Email: ssafe{at}cvm.tamu.edu

Betulinic acid (BA) is a phytochemical triterpenoid acid from bark extracts and is cytotoxic to cancer cells and tumors. We modified the A-ring of BA to give a 2-cyano-1-en-3-one moiety and the effects of the 2-cyano-lup-1-en-3-oxo-20-oic acid (CN-BA), 2-cyano derivative of BA, and its methyl ester (CN-BA-Me) were investigated in colon and pancreatic cancer cells. Both CN-BA and CN-BA-Me were highly cytotoxic to Panc-28 pancreatic and SW480 colon cancer cells. CN-BA and CN-BA-Me also induced differentiation in 3T3-L1 adipocytes, which exhibited a characteristic fat droplet accumulation induced by peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists. Based on these results, we investigated the activities of CN-BA and CN-BA-Me as PPAR{gamma} agonists using several receptor-mediated responses including activation of transfected PPAR{gamma}-responsive constructs, induction of p21 in Panc-28 cells and induction of caveolin-1 and Krüppel-like factor 4 in colon cancer cells. The results clearly demonstrated that both CN-BA and CN-BA-Me activated PPAR{gamma}-dependent responses in colon (caveolin-1) and pancreatic (p21) cancer cells, whereas induction of KLF4 by these compounds in colon cancer cells was PPAR{gamma} independent and also dependent on cell context. The PPAR{gamma} agonist activities of CN-BA and CN-BA-Me were structure-, response/gene- and cell context-dependent suggesting that these compounds are a novel class of selective PPAR{gamma} modulators with potential for clinical treatment of colon and pancreatic cancer.

Abbreviations: BA, betulinic acid; C-DIM, methylene-substituted diindolylmethanes; CDDO, 2-cyano-3,12-dioxo-18ß-oleana-1,19-diene-28-oic acid; ß-CDODA, 2-cyano-3,12-dioxo-18ß-olean-1,12-diene-30-oic acid; CN-BA, 2-cyano-lup-1-en-3-oxo-20-oic acid; CN-BA-Me, methyl ester of CN-BA; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; FBS, fetal bovine serum; ß-GAL, ß-Galactosidase; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; TBST, Tris-buffered saline containing Tween-20

{dagger} Both authors contributed equally to this work.

Received June 8, 2007; revised August 13, 2007; accepted August 13, 2007.


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