OBJECTIVE:
To investigate the combined effects of
cisplatin and the
histone deacetylase (HDAC) inhibitors
suberoylanilide hydroxamic acid (SAHA) or sirtinol on
HeLa cells and assess the mechanism underlying
HDAC inhibitor-
cisplatin synergy.
METHODS:
The
antineoplastic actions of
cisplatin, SAHA and sirtinol, alone and in combination, were evaluated using the tetrazolium
dye-based MTT
cell proliferation assay, DAPI nuclear
staining and cytotoxicity
analysis.
RESULTS:
Exposure to
cisplatin, SAHA or sirtinol alone induced a
dose-dependent reduction in
HeLa cell viability. Combined
treatment with
cisplatin and SAHA or sirtinol was significantly more cytotoxic than
cisplatin alone. Individually,
cisplatin, SAHA and sirtinol activated
caspase-3 and induced
apoptosis, but the effects of combined
treatment were greater. Importantly, both
HDAC inhibitors dose-dependently inhibited the expression of the antiapoptotic
proteins Bcl-2 and
x-linked inhibitor of apoptosis protein (XIAP).
CONCLUSION:
The combination of
cisplatin and SAHA or sirtinol had synergistic effect on the
HeLa cell viability. This potentiation of
cisplatin activity was associated with
HDAC inhibitor-mediated
down-regulation of Bcl-2 and XIAP. These may result from the
relaxation of
chromatin by these
HDAC inhibitors that increase
cisplatin sensitivity by enhancing the accessibility of
DNA to
cisplatin and transcriptional regulators.