Abstract
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 |
|---|---|
| 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 |
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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 journal › Article
}
TY - JOUR
T1 - Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types
AU - Green, S. R.
AU - Choudhary, A. K.
AU - Fleming, I. N.
PY - 2010/11
Y1 - 2010/11
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.
KW - animals
KW - antineoplastic combined chemotherapy protocols
KW - arabinonucleosides
KW - cell death
KW - cell line, tumor
KW - cytosine
KW - female
KW - histone deacetylase inhibitors
KW - humans
KW - hydroxamic acids
KW - leukemia, myeloid, acute
KW - mice
KW - mice, nude
KW - neoplasms
KW - xenograft model antitumor assays
U2 - 10.1038/sj.bjc.6605922
DO - 10.1038/sj.bjc.6605922
M3 - Article
VL - 103
SP - 1391
EP - 1399
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 9
ER -