Sodium phenylacetate induces growth inhibition and Bcl-2 down-regulation and apoptosis in MCF7ras cells in vitro and in nude mice.
Using a highly tumorigenic human breast cancer model (Ha-ras-transfected MCF7 cell line) we analyzed the efficacy of the differentiation-inducing agent sodium phenylacetate (NaPA), both in vitro and in vivo. NaPA-treated MCF7ras cells showed dose-dependent growth inhibition from 2.5 to 15 mM without apparent toxicity. Western blot analysis showed a Bcl-2 down-regulation after 48 h treatment with 5 mM NaPA, together with apparition of apoptotic nuclei by DAPI staining. Mice bearing MCF7ras xenografts (n = 40) were treated for 2 weeks through s.c.-delivering osmotic pumps, followed by 6 weeks of daily i.p. NaPA administration. After 3 weeks, the treated tumors showed growth arrest without regression for the whole observation time, e.g., 12 weeks. Immunohistochemical analysis showed Bcl-2 down-regulation and differentiation patterns: decrease of Ki-67 and increase of steroid receptors (estrogen and progesterone receptors) compared to controls. Cells cultured from treated tumors (II.b) displayed pseudotrabecular disposition as MCF7ras cells treated in vitro. They also showed a higher NaPA sensitivity, together with 70% Bcl-2 down-regulation as compared to the derived cells of untreated tumors (II.a). When reinjected into nude mice, II.b cells induced only one poorly vascularized, noninvasive tumor (8%) with lower proliferation index, 100% progesterone receptor positive cells, and 35% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei, as compared to 100% induction of highly vascularized and invasive tumors with 3% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei induced by II.a cells.
Adam
L
L
Institut d'Oncologie Moléculaire et Cellulaire Humaine, Bobigny, France.
Crépin
M
M
Savin
C
C
Israël
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D011905:Genes, ras; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010648:Phenylacetates / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D010648:Phenylacetates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C025136:phenylacetic acid