CHK2 is involved in the p53-independent radiosensitizing effects of valproic acid

Abstract

Radiotherapy is an effective treatment for the majority of types of localized solid cancer. However, the risk of side effects to the surrounding normal tissues limits radiotherapeutic approaches. Whilst the mechanism of action of valproic acid, an inhibitor of histone deacetylase, remains unknown, the inhibitor is a potential antineoplastic radiosensitizer. The present study demonstrated the in vitro radiosensitizing effects of valproic acid on the human breast cancer MCF7 cell line, and revealed that valproic acid increased the level of DNA breakage, apoptosis and senescence. In addition, western blot analyses revealed that valproic acid induced tumor suppressor protein (p)53 and p21 expression, and activated checkpoint kinase 2 (CHK2) in MCF7 cells and primary mouse embryonic fibroblasts. Notably, treatment with valproic acid also induced increases in the level of p21 protein levels and CHK2 activity in p53-null colon cancer HCT116 cells. Furthermore, the present study demonstrated that valproic acid-induced radiosensitization was largely dependent on the activity of CHK2. The results of the present study reveal that valproic acid may exhibit clinical utility with respect to increasing the anticancer efficacy of radiotherapy by affecting the level of p53.

A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments

“…While these pathways appear straightforward in reviews 36 , the genetic evidence regarding the cell-type specificity of CHEK2 and P53 loss of function adds further confusion because MEFs grown from knockout mice suggest that ATM and P53 but not CHEK2 are required for cell cycle arrest following irradiation 37 . Moreover, in some cancer cell lines, CHEK2 affects cell viability following DNA damage in a TP53 independent manner 38 – 40 . Finally, while CHEK1 is likely a common essential gene in humans, TP53 is not 23 .…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Recent in vitro studies in cell lines have shown VPA to be a radiosensitizer in melanoma, breast cancer, osteosarcoma and colorectal cancer . Several in vivo and in vitro studies as well as clinical studies have also indicated that VPA has radiosensitizing effects for gliomas and is radioprotective to normal brain tissue .…”

Chk2 deficiency alleviates irradiation‐induced taste dysfunction by inhibiting p53‐dependent apoptosis

“…Chk2‐deficient mice exhibited resistance to irradiation‐induced cellular apoptosis (Takai et al., ). Also, the radiosensitizing effects induced by valproic acid on human breast cancer were dependent on the activation of Chk2 (Choo et al., ).…”