Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types

S. R. Green, A. K. Choudhary, I. N. Fleming

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Alternative treatments are needed for elderly patients with acute myeloid leukaemia, as the disease prognosis is poor and the current treatment is unsuitable for many patients.

Methods: In this study, we investigated whether combining the nucleoside analogue sapacitabine with histone deacetylase (HDAC) inhibitors could be an effective treatment. Synergy and mode-of-action analysis were studied in cultured cell lines and the efficacy of the combination was confirmed in a xenograft model.

Results: CNDAC (1-(2-C-cyano-2-deoxy-ß-D-arabino-pentofuranosyl)-cytosine), the active component of sapacitabine, synergised with vorinostat in cell lines derived from a range of tumour types. Synergy was not dependent on a specific sequence of drug administration and was also observed when CNDAC was combined with an alternative HDAC inhibitor, valproate. Flow cytometry and western blot analysis confirmed that the combination induced a significant increase in apoptosis. Mode-of-action analysis detected changes in Bcl-xl, Mcl-1, Noxa, Bid and Bim, which are all regulators of the apoptotic process. The sapacitabine/vorinostat combination demonstrated significant benefit compared with the single-agent treatments in an MV4-11 xenograft, in the absence of any observed toxicity.

Conclusion: Sapacitabine and HDAC inhibitors are an effective drug combination that is worthy of clinical exploration.
Original languageEnglish
Pages (from-to)1391-1399
Number of pages9
JournalBritish Journal of Cancer
Volume103
Issue number9
Early online date5 Oct 2010
DOIs
Publication statusPublished - Nov 2010

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Histone Deacetylase Inhibitors
Cell Death
Cytosine
Heterografts
Neoplasms
Noxae
Cell Line
Valproic Acid
Drug Combinations
Therapeutics
Nucleosides
Acute Myeloid Leukemia
Cultured Cells
Flow Cytometry
Western Blotting
Apoptosis
sapacitabine
Pharmaceutical Preparations
vorinostat

Keywords

  • animals
  • antineoplastic combined chemotherapy protocols
  • arabinonucleosides
  • cell death
  • cell line, tumor
  • cytosine
  • female
  • histone deacetylase inhibitors
  • humans
  • hydroxamic acids
  • leukemia, myeloid, acute
  • mice
  • mice, nude
  • neoplasms
  • xenograft model antitumor assays

Cite this

Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. / Green, S. R.; Choudhary, A. K.; Fleming, I. N.

In: British Journal of Cancer, Vol. 103, No. 9, 11.2010, p. 1391-1399.

Research output: Contribution to journalArticle

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abstract = "Background: Alternative treatments are needed for elderly patients with acute myeloid leukaemia, as the disease prognosis is poor and the current treatment is unsuitable for many patients. Methods: In this study, we investigated whether combining the nucleoside analogue sapacitabine with histone deacetylase (HDAC) inhibitors could be an effective treatment. Synergy and mode-of-action analysis were studied in cultured cell lines and the efficacy of the combination was confirmed in a xenograft model. Results: CNDAC (1-(2-C-cyano-2-deoxy-{\ss}-D-arabino-pentofuranosyl)-cytosine), the active component of sapacitabine, synergised with vorinostat in cell lines derived from a range of tumour types. Synergy was not dependent on a specific sequence of drug administration and was also observed when CNDAC was combined with an alternative HDAC inhibitor, valproate. Flow cytometry and western blot analysis confirmed that the combination induced a significant increase in apoptosis. Mode-of-action analysis detected changes in Bcl-xl, Mcl-1, Noxa, Bid and Bim, which are all regulators of the apoptotic process. The sapacitabine/vorinostat combination demonstrated significant benefit compared with the single-agent treatments in an MV4-11 xenograft, in the absence of any observed toxicity. Conclusion: Sapacitabine and HDAC inhibitors are an effective drug combination that is worthy of clinical exploration.",
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N2 - Background: Alternative treatments are needed for elderly patients with acute myeloid leukaemia, as the disease prognosis is poor and the current treatment is unsuitable for many patients. Methods: In this study, we investigated whether combining the nucleoside analogue sapacitabine with histone deacetylase (HDAC) inhibitors could be an effective treatment. Synergy and mode-of-action analysis were studied in cultured cell lines and the efficacy of the combination was confirmed in a xenograft model. Results: CNDAC (1-(2-C-cyano-2-deoxy-ß-D-arabino-pentofuranosyl)-cytosine), the active component of sapacitabine, synergised with vorinostat in cell lines derived from a range of tumour types. Synergy was not dependent on a specific sequence of drug administration and was also observed when CNDAC was combined with an alternative HDAC inhibitor, valproate. Flow cytometry and western blot analysis confirmed that the combination induced a significant increase in apoptosis. Mode-of-action analysis detected changes in Bcl-xl, Mcl-1, Noxa, Bid and Bim, which are all regulators of the apoptotic process. The sapacitabine/vorinostat combination demonstrated significant benefit compared with the single-agent treatments in an MV4-11 xenograft, in the absence of any observed toxicity. Conclusion: Sapacitabine and HDAC inhibitors are an effective drug combination that is worthy of clinical exploration.

AB - Background: Alternative treatments are needed for elderly patients with acute myeloid leukaemia, as the disease prognosis is poor and the current treatment is unsuitable for many patients. Methods: In this study, we investigated whether combining the nucleoside analogue sapacitabine with histone deacetylase (HDAC) inhibitors could be an effective treatment. Synergy and mode-of-action analysis were studied in cultured cell lines and the efficacy of the combination was confirmed in a xenograft model. Results: CNDAC (1-(2-C-cyano-2-deoxy-ß-D-arabino-pentofuranosyl)-cytosine), the active component of sapacitabine, synergised with vorinostat in cell lines derived from a range of tumour types. Synergy was not dependent on a specific sequence of drug administration and was also observed when CNDAC was combined with an alternative HDAC inhibitor, valproate. Flow cytometry and western blot analysis confirmed that the combination induced a significant increase in apoptosis. Mode-of-action analysis detected changes in Bcl-xl, Mcl-1, Noxa, Bid and Bim, which are all regulators of the apoptotic process. The sapacitabine/vorinostat combination demonstrated significant benefit compared with the single-agent treatments in an MV4-11 xenograft, in the absence of any observed toxicity. Conclusion: Sapacitabine and HDAC inhibitors are an effective drug combination that is worthy of clinical exploration.

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