Growth inhibitory effects and radiosensitization induced by fatty aromatic acids 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 modulate the expression of genes implicated in tumor growth, metastasis, immunogenicity, 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. The effects of PA and PB on the proliferative activity and apoptosis induction in cervical tumor tissue was investigated. Both PA and PB exhibited a time- and dose-dependent antiproliferative activity in SW756 and ME180 cell lines: after 72-h treatment, the IC50 (concentration able to inhibit 50% of cell 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 obtained from patients affected by squamous cervical cancer, both drugs resulted in a marked reduction of the percentage of bromodeoxyuridine-labeled cells compared with untreated samples [19.0 +/- 1.63% in untreated tissues with respect to 1.30 +/- 0.54% and 4.20 +/- 2.50% of stained cells after treatment 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. Finally, 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 p21ras and rhoB proteins in the membrane fraction of cells exposed to PA and PB was observed. When farnesol, which is able to circumvent the enzymatic step inhibited by PA and PB, was added to the medium only a partial reversal of the growth inhibition and potentiation of sensitivity to radiation induced by PA and PB were found. In conclusion, the growth inhibitory properties of fatty aromatic acids suggest that these molecules could represent the prototype of a new class of compounds with some therapeutic potential in cervical cancer.
Ferrandina
G
G
Department of Gynecology/Obstetrics, Catholic University, Rome, Italy.
Filippini
P
P
Ferlini
C
C
Maggiano
N
N
Stoler
A B
AB
Fruscella
E
E
Mozzetti
S
S
Mancuso
S
S
Freedman
R S
RS
Scambia
G
G
Ranelletti
F O
FO
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007633:Keratins / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005227:Fatty Acids; D010648:Phenylacetates; D010654:Phenylbutyrates; D011838:Radiation-Sensitizing Agents; D007633:Keratins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020743:rhoB GTP-Binding Protein; C025136:phenylacetic acid; D001973:Bromodeoxyuridine; D002945:Cisplatin