Ornithine decarboxylase activity in tumor cell lines correlates with sensitivity to cell death induced by histone deacetylase inhibitors.
Inhibitors of histone deacetylases (HDAC) show significant promise as targeted anticancer agents against a variety of hematologic and solid tumors. HDAC inhibitors arrest the growth of primary cells, but they induce apoptosis or differentiation of tumor cells. Although the precise mechanism is unknown, differences in cell cycle checkpoints and chromatin structure may be responsible. Cellular polyamines regulate both cell cycle progression and chromatin structure. In tumors, polyamines are abundantly produced because of increased activity of the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase (ODC). To determine if polyamines contribute to the cellular response to HDAC inhibitors, we inhibited ODC activity with alpha-difluoromethylornithine. Polyamine depletion increased resistance to apoptosis induced by HDAC inhibitors. In addition, we found that ODC activity levels correlated with sensitivity to HDAC inhibitors in a panel of tumor cell lines. We conclude that polyamines participate in the cellular response to HDAC inhibitors and that ODC activity correlates with sensitivity to HDAC inhibitor-induced apoptosis. Thus, elevated polyamine levels might be a biomarker for tumor sensitivity to HDAC inhibitor-induced apoptosis. These findings warrant clinical evaluation of tumor samples to determine if high ODC activity levels predict sensitivity to HDAC inhibitors.
Saunders
Laura R
LR
Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, USA. everdin@gladstone.ucsf.edu
Verdin
Eric
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism
D000970:Antineoplastic Agents; D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C012589:trichostatin A; D006655:Histone Deacetylases; D009955:Ornithine Decarboxylase; D000518:Eflornithine