Dual PPARgamma/alpha agonist has potent anticancer activity.

Abstract

We have previously shown (Clin Cancer Res 10:7238, 2004) that troglitazone reduces breast cancer cell growth in part by inducing a cellular acidosis as a result of inhibiting NHE activity. The present study focuses on a dual PPARγ/α agonist KT6-207 and its ability to induce cellular acidosis and inhibit DNA synthesis in MCF-7 and MDA 231 breast cancer cell lines. The recovery from an acid pulse (20mM NH4CL) assayed using BCECF was 2x faster in the faster growing 231 than MCF-7cells (0.46± 0.06 vs 0.23± 0.05 ΔpHi/min) and TRO (25uM) slowed the rate of recovery in both cell lines. In contrast KT6-207 (25uM) blocked the recovery and converted it to an acidifying response(−0.21± 0.08 and −0.05± 0.02 pHi/min respectively). In both cell lines KT6-207 was a more potent inhibitor of DNA synthesis than TRO reducing 3H-thy incorporation by 66± 8 and 91± 12 % compared to 22 ± 5 and 67 ± 9% in MCF-7 and MDA -231 respectively (all p<0.05 vs control with p<0.01 and p<0.05 for KT6-207 vs TRO in the cell lines respectively). As an index of cellular acidosis, both KT6-207 and TRO increased (p<0.05) NH4+ production (1,774± 120 to 2,839± 289 and 2,150± 180nmol/mg in MCF-7 and 1,899± 93 to 2,654± 116 and 3,027 ±239nmol/mg MDA-231 cell lines). However, only KT6-207 increased acid production in the latter from 36.8±5.8 to 59.0±9.1umol/mg (p<0.01); TRO did not increase acid production (39.7±6.7umol/mg). Our findings are consistent with KT6-207 being a more effective inhibitor of breast cancer growth via inhibiting acid extrusion while simultaneously enhancing acid production.