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 γ (PPARγ) agonists. Based on these results, we investigated the activities of CN-BA and CN-BA-Me as PPARγ agonists using several receptor-mediated responses including activation of transfected PPARγ-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 PPARγ-dependent responses in colon (caveolin-1) and pancreatic (p21) cancer cells, whereas induction of KLF4 by these compounds in colon cancer cells was PPARγ independent and also dependent on cell context. The PPARγ 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 PPARγ modulators with potential for clinical treatment of colon and pancreatic cancer. [ABSTRACT FROM AUTHOR]
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