Tumor growth inhibition, apoptosis, and Bcl-2 down-regulation of MCF-7ras tumors by sodium phenylacetate and tamoxifen combination.
We demonstrated previously the antitumoral and antiproliferative effects of sodium phenylacetate (NaPA) on malignant breast epithelial MCF-7ras cells and its lack of toxicity. The present in vivo protocols were as follows: (1) a control group; (2) a NaPA-receiving group (450 mg/kg) through s.c. osmotic pumps (ALZA Corp.) for 2 weeks, followed by 2 weeks with no treatment; and (3) a tamoxifen (TAM)-receiving group (20 mg/kg two times per week). The second group was further divided as follows: (a) a group receiving same doses of NaPA; (b) a TAM-receiving group; and (c) a group receiving both NaPA and TAM. Although tumors treated by TAM alone (group 3) showed progressive regrowth after 6 weeks, indicating an escape from antiestrogen inhibition, the TAM-administered group, following 2 weeks of NaPA pretreatment (group 2b), showed significant tumor regression of about 40% after 8 weeks. This effect was amplified to over 60% (P < 0.001) by simultaneous administration of the two drugs (group 2c). The last group displayed about 30% apoptotic-like nuclei, together with lower proliferation index, and less tumor vascularization, as compared to less than 5% terminal deoxytransferase-mediated dUTP-X nick end labeling-positive nuclei, highly vascularized tumors, in the TAM-treated group. Furthermore, in vitro administration of 4-OH-tamoxifen induced a Bcl-2 up-regulation in MCF-7ras cells, which was completely abolished by NaPA pretreatment. The combination of NaPA and OHT induced significant cell differentiation with cell cycle accumulation in the G0-G1 phase.
Adam
L
L
Institut d'Oncologie Moléculaire et Cellulaire Humaine, Bobigny, France.
Crépin
M
M
Isräel
L
L
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens; D005260:Female; D011905:Genes, ras; D006131:Growth Inhibitors / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D004967:Estrogens; D006131:Growth Inhibitors; D010648:Phenylacetates; D019253:Proto-Oncogene Proteins c-bcl-2; D013629:Tamoxifen; D015689:Oncogene Protein p21(ras); C025136:phenylacetic acid