Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown benefit in treating diabetes mellitus, atherosclerosis and cancer. However, widespread use of thiazolidinediones (TZDs), the clinically used synthetic PPARgamma agonists, has been limited by adverse cardiovascular effects. Consequently, numerous novel non-TZD compounds were synthesized and antidiabetic efficacy was evaluated to identify PPARgamma agonists for potential clinical use. On the other hand, many studies have documented that the antitumor activity of PPARgamma agonists is PPARgamma independent. Here we hypothesized that there might exist some compounds with less PPARgamma agonistic activity or antidiabetic efficacy but potent antitumor activity. In this study, we evaluated the PPARgamma agonistic and antitumor activity of several newly synthesized alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as PPARgamma agonists in a panel of human cancer cell lines, which showed promising antitumor activity without appreciable PPARgamma agonistic activity. The results of MTT assay revealed that cell viability was inhibited in a dose dependent manner with IC(50) 17.1-55.1 microM for all the novel compounds and rosiglitazone (17.2-165 microM). They induced cell cycle arrest and apoptosis tested by Flow Cytometry. In conclusion, our findings demonstrate that these compounds have potent in vitro cytotoxicity, the possible mechanism of which is through induction of apoptosis and cell cycle arrest.