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Carcinogenesis Advance Access published online on August 27, 2007
Carcinogenesis, 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,*, Sabitha Papineni1,*, 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
2 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466
3 Department of Chemistry, South Dakota State University, Brookings, SD 57007

Send all correspondence to: Stephen Safe, Distinguished Professor of Toxicology, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Vet. Res. Bldg. 410, College Station, TX 77843-4466 ,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 derivative of BA (CN-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) 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.

Key Words: Betulinic acid • 2-cyanobetulinic acid analogs • PPAR{gamma} • cancer cells

* Both authors contributed equally to this work.

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


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