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.
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 language | English |
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Pages (from-to) | 1391-1399 |
Number of pages | 9 |
Journal | British Journal of Cancer |
Volume | 103 |
Issue number | 9 |
Early online date | 5 Oct 2010 |
DOIs | |
Publication status | Published - 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