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Vorinostat Induces Reactive Oxygen Species and DNA Damage in Acute Myeloid Leukemia Cells

By Luca A. Petruccelli, Daphné Dupéré-Richer, Filippa Pettersson, Hélène Retrouvey, Sophia Skoulikas and Wilson H. Miller


Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Additionally, AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a reduction in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  1. (1998). A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases.
  2. (2009). A phase 2 study of vorinostat in acute myeloid leukemia.
  3. (2010). A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. Invest New Drugs.
  4. (2006). Actions of a histone deacetylase inhibitor NSC3852 (5-nitroso-8-quinolinol) link reactive oxygen species to cell differentiation and apoptosis in MCF-7 human mammary tumor cells.
  5. (2006). Anticancer activities of histone deacetylase inhibitors.
  6. (2007). Attenuated DNA damage repair by trichostatin A through BRCA1 suppression.
  7. (2005). Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species.
  8. (2008). Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control.
  9. (2003). DNA double-strand breaks and gamma-H2AX signaling in the testis.
  10. (2002). Dynamics and diversions in base excision DNA repair of oxidized abasic lesions.
  11. (2007). FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.
  12. (2007). Global chromatin compaction limits the strength of the DNA damage response.
  13. (2007). HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination.
  14. (2007). HDAC inhibitors: a potential new category of anti-tumor agents.
  15. (2007). HDAC inhibitors: clinical update and mechanism-based potential.
  16. (2008). Histone deacetylase inhibitor SAHA induces ERalpha degradation in breast cancer MCF-7 cells by CHIP-mediated ubiquitin pathway and inhibits survival signaling.
  17. (2010). Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo.
  18. (2006). Histone deacetylase inhibitors (HDI) cause DNA damage in leukemia cells: a mechanism for leukemia-specific HDI-dependent apoptosis?
  19. (2009). Histone deacetylase inhibitors and genomic instability.
  20. (2008). Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosis.
  21. (2005). Histone deacetylase inhibitors and malignant melanoma.
  22. (2008). Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs.
  23. (2001). Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17).
  24. (2001). Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia.
  25. (2005). Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity.
  26. (2007). Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation.
  27. (2000). Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells.
  28. (1999). Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53.
  29. (2010). Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage.
  30. (2003). Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA.
  31. (2006). Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor.
  32. (2005). Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair.
  33. (2009). Lysine acetylation targets protein complexes and co-regulates major cellular functions.
  34. (2008). OSUHDAC42, a histone deacetylase inhibitor, blocks prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate model.
  35. (2007). PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway.
  36. (2008). Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes.
  37. (2007). Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies.
  38. (2005). Prospects: histone deacetylase inhibitors.
  39. (2002). Response to histone deacetylase inhibition of novel PML/RARalpha mutants detected in retinoic acid-resistant APL cells.
  40. (2009). Romidepsin for the treatment of cutaneous T-cell lymphoma.
  41. (2004). Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair.
  42. (2002). Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells.
  43. (1998). Temporal relationship of CDK1 activation and mitotic arrest to cytosolic accumulation of cytochrome C and caspase-3 activity during Taxol-induced apoptosis of human AML HL-60 cells.
  44. (2006). The comet assay: a method to measure DNA damage in individual cells.
  45. (2001). The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species.
  46. (2007). The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation.
  47. (2010). The molecular signature of oncofusion proteins in acute myeloid leukemia.
  48. (2001). Transcription therapy for cancer.
  49. (2004). Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications.