Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: Efficacy and underlying mechanisms

Abstract

Histone deacetylase (HDAC) inhibitors can radiosensitize cancer cells. Radiation is critical in high-risk neuroblastoma treatment, and combinations of HDAC inhibitor vorinostat and radiation are proposed for neuroblastoma trials. Therefore, we investigated radiosensitizing effects of vorinostat in neuroblastoma. Treatment of neuroblastoma cell lines decreased cell viability and resulted in additive effects with radiation. In a murine metastatic neuroblastoma in vivo model vorinostat and radiation combinations decreased tumor volumes compared to single modality. DNA repair enzyme Ku-86 was reduced in several neuroblastoma cells treated with vorinostat. Thus, vorinostat potentiates anti-neoplastic effects of radiation in neuroblastoma possibly due to down-regulation of DNA repair enzyme Ku-86.

Molecular Pathways: Old Drugs Define New Pathways: Non-Histone Acetylation at the Crossroads of the DNA Damage Response and Autophagy

“…Increased accessibility to DNA-damaging agents, however, is unlikely to be the only mechanism responsible for the effects of treatment with HDAC inhibitors. HDACs have also been shown to regulate the transcription rate and the protein levels of several components of the DDR cascade (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

“…The combination of DNA-damaging agents with HDAC inhibitors induces a higher number and prolonged duration of phosphorylated histone H2AX (gH2AX) nuclear foci, which are classical markers of DSBs (12,17,18,21,23,26,(28)(29)(30). Vorinostat has been shown to act as a radiosensitizer of lung cancer and melanoma cells through a strong inhibitory effect on the NHEJ pathway (22,31).…”

“…In prostate and glioma cancer cells, radiosensitization by vorinostat is achieved by attenuating the expression of homologous recombination DNA repair genes (16,18). Inhibition of the expression of radiation-induced DNArepair proteins (RAD50, DNA-PK, Rad51, Ku80, and Ku86) contributes to vorinostat-mediated radiosensitization of pancreatic, osteosarcoma, rhabomyosarcoma, and neuroblastoma cells (14,17,21).…”

“…CtIP deacetylation by SIRT6 was shown to positively regulate DSB repair in humans, but in this case, its effects on protein stability were not analyzed (47). It would be interesting to see if HDAC inhibitorinduced hyperacetylation and/or autophagy has a role in the downregulation of the several DDR proteins associated with the increased cell sensitivity to DNAdamaging agents upon treatment with HDAC inhibitors (13,14,(16)(17)(18)(21)(22)(23)(24).…”

Recurrent Neuroblastoma

“…HDAC inhibition leads to histone acetylation, opening of chromatin structure, and reactivation of previously silenced genes (Johnstone, 2002). In NB, HDAC inhibitors have been shown to induce apoptosis and impair VEGF production (MuhlethalerMottet et al, 2008), restore the p53 pathway (Condorelli et al, 2008), synergize with retinoic acid to inhibit growth (Coffey et al, 2001), and enhance RT (S. Mueller et al, 2011). In a phase I trial of vorinostat, one CR was observed in a NB patient receiving vorinostat in combination with 13-cis-retinoic acid (Fouladi et al, 2010).…”