Breast cancer patients with HER-2 positive or estrogen receptor negative tumors 
have a poor prognosis because these tumors are aggressive and respond poorly to 
standard therapies. Histone deacetylase (HDAC) inhibitors have been shown to 
decreased cell survival, which suggests that HDAC inhibitors may be developed 
for preventing and treating breast cancer. Curcumin has anti-inflammatory and 
proapoptotic effects in cancer cells. We determined whether the HDAC inhibitor, 
Tricostatin A (TSA) in combination with curcumin would produce greater 
antiproliferative and apoptotic effects than either agent alone. Increasing the 
concentration of curcumin from 10 to 20 µM enhanced the growth inhibitory 
effects of the combination in SkBr3 and 435eB breast cancer cells, which was 
accompanied by decreased viability along with decreased phosphorylation of ERK 
and Akt. The decreased cell viability observed in SkBr3 cells when curcumin was 
combined with TSA led to a G0/G1 cell cycle arrest and increased p21 and p27, 
and decreased Cyclin D1 protein expression. The combination induced cleavage of 
caspase 3 and poly(ADP-ribose) polymerase-1, suggesting that cell death occurred 
by apoptosis. There were no changes in protein expression of Bcl2, Bax, or 
Bcl-xL and decreased expression of p53. The combination increased protein 
expression of phosphorylated JNK and phosphorylated p38. Pharmacological 
inhibition of JNK, but not p38, attenuated the decreased viability induced by 
the curcumin and TSA combination. We conclude that p53 independent apoptosis 
induced by combining curcumin and TSA involves JNK activation. These findings 
provide a rationale for exploring the potential benefits of the combination of 
curcumin with TSA for treatment of breast cancer.