Pharmacologic options for patients with
castration-resistant
prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow
tumor growth. Therefore, the growth-blocking potential of the
histone deacetylase-inhibitor LBH589 and the multiple
tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of
prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of
LBH589 and/or
TKI258.
Tumor cell growth, cell cycle regulating
proteins, HDAC3- and HDAC4-expression and
histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting.
LBH589 dose-dependently blocked
prostate cancer cell growth. In contrast,
TKI258 did not down-regulate
tumor cell growth up to a 1,000 nM dosage.
LBH589 elevated
histone H3 and H4 acetylation. The cell cycle regulators
cyclin B,
cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor
proteins p21 and p27 were up-regulated in LNCaP by
LBH589.
TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated
cyclin B,
cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in
cyclin and cdk caused by
TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in
TKI258 non-responsiveness. The
LBH589/
TKI258-combination was not superior to the
LBH589 single-
drug use in terms of growth reduction. Obviously,
TKI258 did not enhance the sensitivity of
prostate cancer cells towards an HDAC based regimen. Therefore, the
LBH589/
TKI258-combination probably does not provide an optimum strategy in fighting advanced
prostate cancer.