title: 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.
abstract: 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 (PPARgamma) agonists. Based on these results, we investigated the activities of CN-BA and CN-BA-Me as PPARgamma agonists using several receptor-mediated responses including activation of transfected PPARgamma-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 PPARgamma-dependent responses in colon (caveolin-1) and pancreatic (p21) cancer cells, whereas induction of KLF4 by these compounds in colon cancer cells was PPARgamma independent and also dependent on cell context. The PPARgamma 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 PPARgamma modulators with potential for clinical treatment of colon and pancreatic cancer.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center,Houston, TX 77030-3303, USA.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Chintharlapalli
authors.forename: Sabitha
authors.initials: S
authors.lastname: Papineni
authors.forename: Shengxi
authors.initials: S
authors.lastname: Liu
authors.forename: Indira
authors.initials: I
authors.lastname: Jutooru
authors.forename: Gayathri
authors.initials: G
authors.lastname: Chadalapaka
authors.forename: Sung-dae
authors.initials: SD
authors.lastname: Cho
authors.forename: Rajesh S
authors.initials: RS
authors.lastname: Murthy
authors.forename: Youngjae
authors.initials: Y
authors.lastname: You
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: C525836:2-cyanolup-1-en-3-oxo-20-oic acid; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D047495:PPAR gamma; D014315:Triterpenes