Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells.

Background: Histone deacetylase inhibitors (HDACis) are promising anticancer drugs; however, the molecular mechanisms leading to HDACi-induced cell death have not been well understood and no clear mechanism of resistance has been elucidated to explain limited efficacy of HDACis in clinical trials.

Methods And Findings: Here, we show that protein levels of checkpoint kinase 1 (Chk1), which has a major role in G(2) cell cycle checkpoint regulation, was markedly reduced at the protein and transcriptional levels in lung cancer cells treated with pan-and selective HDACis LBH589, scriptaid, valproic acid, apicidin, and MS-275. In HDACi treated cells Chk1 function was impaired as determined by decreased inhibitory phosphorylation of cdc25c and its downstream target cdc2 and increased expression of cdc25A and phosphorylated histone H3, a marker of mitotic entry.

VEGF-associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy.

Purpose: In this study, the efficacy of combining ZD6474 (Zactima), a vascular endothelial growth factor (VEGF) receptor 2-associated tyrosine kinase inhibitor currently undergoing Phase II clinical trial evaluation, with single and fractionated dose radiation exposures was examined in a human colorectal carcinoma model (HT29).

Methods And Materials: HT29 xenograft-bearing mice were treated with either single-dose (10 Gy) or multifraction (2 Gy/day for 2 weeks) radiotherapy alone or in conjunction with a 2-week course of ZD6474 (25 mg/kg). In the single-dose investigation, ZD6474 treatment followed radiotherapy, whereas in the fractionated dose studies the antiangiogenic therapy was given before, after, or concurrent with the radiation.