The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety 
of malignancies. In this investigation, we define the activity of this class of 
inhibitors in combination with traditional cytotoxic chemotherapy in endometrial 
cancer cells. Significant reductions in growth were observed in Ark2 and KLE 
endometrial cancer cells following treatment with paclitaxel, doxorubicin, 
carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined 
treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This 
combination also resulted in significant changes in cell morphology. Using cell 
cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) 
polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most 
dramatic activation of the apoptotic cascade. These effects were also observed 
when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for 
TSA. The anticancer properties of paclitaxel are known to result in part from 
inhibition of microtubule depolymerization, which results in apoptosis. We show 
that TSA administration also stabilizes microtubules via alpha-tubulin 
acetylation. Furthermore, using Western blot and immunohistochemical analysis, 
treatment with TSA/paclitaxel led to a significant increase in acetylated 
tubulin and microtubule stabilization. These effects were confirmed in a mouse 
xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor 
weight compared with either agent alone. This study provides in vivo evidence of 
nonhistone protein acetylation as one possible mechanism by which HDAC 
inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold 
promise for the treatment of serous endometrial carcinoma and other malignancies 
with limited sensitivity to paclitaxel.