Antitumor activity of a novel series of α-aryloxy-α-methylhydrocinnamic acid derivatives as PPAR gamma agonists against a panel of human cancer cell lines

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists have shown benefit in treating diabetes mellitus, atherosclerosis and cancer. However, widespread use of thiazolidinediones (TZDs), the clinically used synthetic PPAR gamma agonists, has been limited by adverse cardiovascular effects. Consequently, numerous novel non-TZD compounds were synthesized and antidiabetic efficacy was evaluated to identify PPAR gamma agonists for potential clinical use. On the other hand, many studies have documented that the antitumor activity of PPAR gamma agonists is PPAR gamma independent. Here we hypothesized that there might exist some compounds with less PPAR gamma agonistic activity or antidiabetic efficacy but potent antitumor activity. In this study, we evaluated the PPAR gamma agonistic and antitumor activity of several newly synthesized alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as PPAR gamma agonists in a panel of human cancer cell lines, which showed promising antitumor activity without appreciable PPAR gamma agonistic activity. The results of MTT assay revealed that cell viability was inhibited in a dose dependent manner with IC50 17.1-55.1 mu M for all the novel compounds and rosiglitazone (17.2-165 mu M). 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.