Sensitization to γ-irradiation-induced cell cycle arrest and apoptosis by the histone deacetylase inhibitor trichostatin A in non-small cell lung cancer (NSCLC) cells

Abstract

Histone deacetylase (HDAC) inhibitors (HDIs) play an important role in the regulation of

gene expression associated with cell cycle and apoptosis and have emerged as promising

anticancer agents. In addition to their intrinsic anticancer properties, some studies have

demonstrated that HDIs can modulate cellular responses to ionizing radiation (IR). Here we

show evidence that co-treatment with the HDI trichostatin A (TSA) radiosensitizes human

non-small cell lung cancer (NSCLC) A549 cells and H1650 cells. Cells were exposed to

γ-irradiation with or without TSA co-treatment. Clonogenic survival was significantly

reduced in cells with TSA co-treatment. In A549 cells, TSA enhanced IR-induced

accumulation of cells in G2/M phase, with upregulated expression of P21waf1/cip1. In addition,

TSA co-treatment caused pronounced apoptosis in irradiated cells, which was accompanied

with P21waf1/cip1 cleavage to a 15 kDa protein. The enhanced apoptotic effect was via

mitochondrial pathway, as indicated by the increased dissipation of mitochondrial

transmembrane potential (MMP) and release of cytochrome c from the mitochondria to the

cytoplasm. Caspase-3 activation was also significantly increased, with accordingly more

cleavage of PARP, associated with the repression of X-linked inhibitor of apoptosis protein

(XIAP). Furthermore, TSA co-treatment impaired DNA repair capacity after IR by

downregulation of Ku70, Ku80 and DNA-PKcs, reflected by enhanced and prolonged

expression of γ-H2AX. Taken together, our results demonstrate that TSA acts as a powerful

radiosensitizer in NSCLC cells by enhancing G2/M cell cycle arrest, promoting apoptosis

through multiple pathways and interfering with DNA damage repair processes.