Modulation of sensitivity to doxorubicin by the histone deacetylase inhibitor sodium butyrate in breast cancer cells.
The histone deacetylase inhibitor sodium butyrate induces several gene products that modify cellular metabolism. Here, we investigated its ability to modulate glutathione-related detoxification enzymes in the breast cancer cell line MCF-7 and a derivative resistant to vincristine (VCREMS). We found that sodium butyrate induced glutathione S-transferase and glutathione-dependent peroxidase activities and triggered glutathione depletion. Expression of MRP1, an ATP-dependent GS-X pump, was unmodified. Moreover, isobologram analysis showed that sodium butyrate sensitized VCREMS to doxorubicin-mediated toxicity. Verapamil, an inhibitor of MRP1, did not significantly affect this chemosensitizing effect, suggesting that the observed toxicity stems from multifactorial mechanisms. Interestingly, synergism between sodium butyrate and doxorubicin was more pronounced in resistant VCREMS cells than in parental sensitive MCF-7 cells.
Louis
Monette
M
Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique (EA 3472) UFR SciFA, Université de Metz, Campus Bridoux, 57070 Metz, France.
Rosato
Roberto R
RR
Battaglia
Eric
E
Néguesque
Adrien
A
Lapotre
Agnès
A
Grant
Steven
S
Bagrel
Denyse
D
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil; D005978:Glutathione