Effect of histone deacetylase inhibitor LAQ824 on antineoplastic action of 5-Aza-2'-deoxycytidine (decitabine) on human breast carcinoma cells.
OBJECTIVE
Epigenetic silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation and chromatin deacetylation provides interesting targets for chemotherapeutic intervention by inhibitors of these events. 5-Aza-2'-deoxycytidine (decitabine, 5AZA-CdR) is a potent demethylating agent, which can reactivate TSGs silenced by aberrant DNA methylation. LAQ824 (LAQ) is a novel inhibitor of histone deacetylase (HDAC) that shows antineoplastic activity and can activate genes that produce cell cycle arrest. Both 5AZA-CdR and LAQ as single agents are currently under clinical investigation in patients with cancer. Previous reports indicate that the "cross-talk" between inhibitors of DNA methylation and HDAC can result in a synergistic activation of silent TSGs. These observations suggest that combination of these inhibitors may be an effective form of epigenetic therapy for breast cancer. The objective of our study was to determine if the combination of 5AZA-CdR and LAQ would show additive or synergistic antineoplastic activity on human MDA-MB-231 and MCF-7 breast carcinoma cells. The antineoplastic activity of these agents was evaluated by clonogenic assay and inhibition of DNA synthesis.


RESULTS
The combination produced greater antineoplastic activity for the MDA-MB-231 tumor cells than either agent alone. For the MCF-7 tumor cells, there were signs of antagonism between 5AZA-CdR and LAQ when administered simultaneously. When a sequential schedule (first 5AZA-CdR followed by LAQ) was used, there were no signs of antagonism of the antineoplastic action for the MCF-7 tumor cells. The mechanism of this interaction is probably due to the reduction of progression of MCF-7 tumor cells into S phase by LAQ. This would interfere with the antineoplastic action of 5AZA-CdR, since it is an S phase specific agent.


CONCLUSIONS
These studies demonstrated the importance of the schedule of administration of 5AZA-CdR and LAQ and may have application for future clinical trials on the treatment of breast cancer with these agents.
Hurtubise
Annie
A
Département de pharmacologie, Centre de recherche pédiatrique, Service d'hématologie-oncologie, Hôpital Sainte-Justine, Université de Montréal, 3175 Côte Sainte-Catherine, H3T 1C5, Montréal, QC, Canada.
Momparler
Richard L
RL
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004247:DNA / Q000096:biosynthesis; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D014411:Neoplastic Stem Cells; D016196:S Phase / Q000187:drug effects; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C477361:LAQ824; D000077209:Decitabine; D004247:DNA; D001374:Azacitidine