Growth inhibitory effects and radiosensitization induced by fatty aromaticacids on human cervical cancer cells

Evidences have been reported that phenylacetic (PA) and phenylbutyric (PB) fatty aromatic acids can exert tumor growth inhibition in vitro and in vivo . Moreover, clinical trials also showed some activity for these drugs to mo dulate the expression of genes implicated in tumor growth, metastasis, immu nogenicity, and to potentiate the efficacy of cytotoxic agents. The aim of the study was to examine the effects of PA and PB on the growth as well as sensitization to cisplatin and radiation in human cervical cancer cells. Th e effects of PA and PB on the proliferative activity and apoptosis inductio n in cervical tumor tissue was investigated. Both PA and PB exhibited a tim e- and dose-dependent antiproliferative activity in SW756 and ME180 cell li nes: after 72-h treatment, the IC50 (concentration able to inhibit 50% of c ell growth) of PB was 1.9 +/- 0.2 mM and 1.5 +/- 0.2 mM in SW756 and ME180 cells, respectively, while the IC50 of PA was 13.0 +/- 1.7 mM and 10.0 +/- 1.2 mM in SW756 and ME180 cells, respectively. In tumor tissue biopsies obt ained from patients affected by squamous cervical cancer, both drugs result ed in a marked reduction of the percentage of bromodeoxyuridine-labeled cel ls compared with untreated samples [19.0 +/- 1.63% in untreated tissues wit h respect to 1.30 +/- 0.54% and 4.20 +/- 2.50% of stained cells after treat ment with PA (30 mM) (P < 0.0001) and PB (5 mM) (P < 0.0001), respectively] . Moreover, analysis of the staining with M30 monoclonal antibody revealed that PA (30 mM) and PB (5 mM) were able to produce a marked increase in the number of stained apoptotic nuclei with respect to untreated samples. Fina lly, PB and PA were shown to enhance the sensitivity of SW756 to radiation and to exert an additive effect when combined with cisplatin. A significant reduction of the processed form of p21(ras) and rhoB proteins in the membr ane fraction of cells exposed to PA and PB was observed. When farnesol, whi ch is able to circumvent the enzymatic step inhibited by PA and PB, was add ed to the medium only a partial reversal of the growth inhibition and poten tiation of sensitivity to radiation induced by PA and PB were found. In con clusion, the growth inhibitory properties of fatty aromatic acids suggest t hat these molecules could represent the prototype of a new class of compoun ds with some therapeutic potential in cervical cancer.