Cancer cells are often characterised by an over-expression of PPARα and γ, members of the nuclear receptor superfamily, which may therefore be potential targets for biological therapy. In this report, we provide data on the in vitro anti-cancer activity of a new series of clobifric acid derivatives with PPARα/γ agonist activities. 10 compounds were synthesized and their effects on cancer cell growth, apoptosis and signalling pathways were evaluated. Breast, colon and liver cancer cell lines (HepG2, MCF7, MDA-MB- 231, HT-29, LoVo and HCT-15) were utilised in all the experiments. All agents showed an IC50 range between 20μM and 100μM; among them, the main active ones were LT127 and LT160 (two enantiomers). They induced apoptosis after 1-2 days exposure, with at least a 20% increase in annexin V positive cells. There was also a slight modification of cell cycle progression, with cells accumulating at the G0/G1 phase. Preliminary results with a specific PPARγ irreversible inhibitor, showed that the relationship between the drugs’ effects and PPARγ activation is cell line dependent. Furthermore, as already reported for troglitazone (the reference compound), 1 day exposure to our compounds stimulated the proliferation pathway, with increased expression of phosphorylated Erk1/2, and inhibited the survival pathway, with increased PTEN expression and consequently reduction of p-Akt expression level, after 1 day-drug exposure. Surprisingly, after 2 days drugs exposure, PTEN was strongly inhibited with a consequent increase of p-Akt level, suggesting that combinations of these drugs with agents acting upstream or downstream of the PI3K/Akt pathway are worth investigation. In HepG2 cells, combination of the PPARγ ligands with gefitinib or rapamycin enhanced growth inhibition and increased apoptosis. Further studies are required to fully evaluate the anti-cancer potential of these clofibric acid derivatives. However, further experiments will clarify if these effects are cell line- and schedule-dependent.

Gefitinib is a trademark of the AstraZeneca group of companies

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA