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

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

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