[PDF][PDF] Sensitization to γ-irradiation-induced cell cycle arrest and apoptosis by the histone deacetylase inhibitor trichostatin A in non-small cell lung cancer (NSCLC) …
F Zhang, T Zhang, Z Teng, R Zhang… - Cancer biology & …, 2009 - Taylor & Francis
F Zhang, T Zhang, Z Teng, R Zhang, JB Wang, QB Mei
Cancer biology & therapy, 2009•Taylor & FrancisHistone 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 …
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 …
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.
Taylor & Francis Online