The invention combines a
microarray and
cell-based screening strategy that enables
rapid identification of possible mechanisms
underpinning the
pharmacology and
toxicology of
drug candidates. The methods of the invention identified unique properties relating to
apoptosis and the anti-
inflammatory response elicited by several
peroxisome proliferator activated
receptor gamma (PPARγ) ligands. The methods illustrate, for example, that PPARγ ligands that are safe and effective drugs (e.g., Actos, Avandia) either do not induce
apoptosis or only modestly induce
apoptosis. Conversely, PPARγ ligands that have failed clinical development (e.g., Ciglitazone; Day, C., Diabet. Med., 16: 179-192 (1999)) or that have been withdrawn from the market (e.g., Troglitazone (Rezulin)) due to hepatotoxicity are potent inducers of apoptosis. The methods of the invention also illustrate that suppression of
gene expression and
protein expression for several pro-
inflammatory factors by some PPARγ ligands occurs as a consequence of apoptotic induction (i.e., apoptosis produces an anti-
inflammatory response). The invention also provides biomarkers for
cellular pathways and methods for stratifying patient groups according to their biomarker expression as well as biomarkers that discriminate safe and effective drugs from compounds that have acute toxicities. These biomarkers provide novel insights into the
mechanism of action and
toxicity for test compounds, including
cell death, anti-inflammatory activity, hepatotoxicity, and carcinogenicity. The methods are highly scalable and have broad application from discovery to the clinic, including compound prioritization, predictive
pharmacology and
toxicology;
mechanism of action studies; and prognostic and
diagnostic biomarker discovery.