Histone Deacetylase Inhibitor: Antineoplastic Agent and Radiation Modulator

Abstract

Inhibitors of histone deacetylases (HDACs) have emerged as a new class of anticancer agents based on their actions in cancer cell growth and cell cycle arrest, terminal differentiation, and apoptosis. Previously, we rationally designed and developed a new class of hydroxamide- and mercaptoacetamide-bearing HDAC inhibitors. A subset of these inhibitors exhibited chemo-radiation sensitizing properties in various human cancer cells. Furthermore, some HDAC inhibitors protected normal cells from radiation-induced damage and extended the survival of mice following total body exposure to lethal dose radiation. Pathological analyses revealed that intestinal and bone marrow cellularities recovered significantly from radiation-induced damage by structural compartments restoration, suggesting the mechanism of action of these HDAC inhibitors. These findings support the hypothesis that epigenetic regulation may play a crucial role in the functional recovery of normal tissues from radiation injuries.

Biological determinants of radioresistance and their remediation in pancreatic cancer

“…Consistent with previous studies in other cancers, mechanistically vorinostat was found to delay DNA repair post-IR (via inhibition of both NHEJ and HR) as well as inhibit constitutive and IR-induced NF-κB and EGFR signaling pathways, [247]. Paradoxically, studies have also demonstrated the ability of HDACIs to radioprotect healthy tissues, particularly cutaneous, intestinal, and bone marrow tissues, both in vitro and in vivo [246]. With this preclinical foundation, two clinical trials, one published and one with unknown status, have tested the effects of HDACIs with CRT in PC [248].…”

“…Preclinical studies using HDAC inhibitors (HDACIs) on PC and various other cancers have demonstrated the role of HDACs in response to and repair of DNA damage [246]. By increasing the amount of radiation-induced DNA damage and slowing DNA repair, along with modulation of p53, pRB, cell cycle regulators, as well as regulators of apoptosis and cell proliferation, HDACIs radiosensitize cancer cells.…”

Opportunities and challenges of radiotherapy for treating cancer

“…Importantly, reports suggest that HDAC inhibitors do not radiosensitize normal cells in the same way as they sensitize cancer cells. 74 In fact, HDAC inhibitors have even been shown to protect against the lethality of whole-body irradiation in mice, 75,93 indicating a possible radiotherapeutic differential. This radioprotection might be due to their anti-inflammatory effects, evidence of which is growing.…”

“…88,89 Others have shown that key DNA-repair molecules including Ku70/Ku80, DNA-PK, RAD50, RAD51, BRCA1/2, and MRE11 are downregulated by vorinostat and other HDAC inhibitors in combination with radiotherapy, leading to RIF persistence. 75,77,[90][91][92] Furthermore, DNArepair-defective cancers are more sensitive to HDAC inhibition. 69 For many reasons, these drugs might make good candidates for combination with radiotherapy, but the mechanisms might be obscure.…”

“…70 Combining radiation with HDAC inhibitors was demonstrated to be a promising approach by findings that these drugs radiosensitize various cancer cell lines in culture and in vivo. [71][72][73][74][75][76][77] This combination approach was first tested in the clinic in 2009, 78 and since then several trials have been initiated and have produced some promising early data. 79 The main rationale presented for the use of these inhibitors is that they prevent HDACs from maintaining tightly packed chromatin that might promote radioresistance.…”