Modulation of cellular radiation responses by histone deacetylase inhibitors

Abstract

Histone deacetylase (HDAC) inhibitors are emerging as a new class of targeted cancer chemotherapeutics. Several HDAC inhibitors are currently in clinical trials and promising anticancer effects at well-tolerated doses have been observed for both hematologic and solid cancers. HDAC inhibitors have been shown to induce cell-cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. However, it is known that these compounds induce varying responses in different cells and biological settings, and identifying their precise mechanisms of action is an area of great interest. Important findings are continually expanding our understanding of the cellular effects of HDAC inhibitors and recent studies will be briefly outlined in this review. In addition to their intrinsic anticancer properties, numerous studies have demonstrated that HDAC inhibitors can modulate cellular responses to other cytotoxic modalities including ionizing radiation, ultraviolet radiation and chemotherapeutic drugs. Hence, there is a growing interest in potential clinical use of HDAC inhibitors in combination with conventional cancer therapies. In this review, the interaction of HDAC inhibitors with other anticancer agents is discussed. The focus of the article is on the different mechanisms by which HDAC inhibitors enhance the sensitivity of cells to the effects of ionizing radiation.

Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents

“…These findings suggest that HDAC6 inhibition increased etoposide or SAHA induced accumulation of DNA DSBs, which may explain, in part, the chemosensitizing effect of HDAC6 inhibition in transformed cells. Synergistic and additive tumor cell apoptosis has been observed when combining pan-HDAC inhibitors with cytotoxic therapies that induce DNA damage (32)(33)(34). Enhanced DNA damage observed in culture with combined inhibitors has been attributed to induction of histone hyperacetylation by the HDAC inhibitor, resulting in a more open chromatin structure, making DNA more susceptible to damage by various toxic agents (35).…”

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…In a short period of time, HDACi have shown promising results in preclinical and clinical trials with low toxicity in certain solid tumors and hematological malignancies (Bolden et al, 2006). In addition to their intrinsic anticancer properties, HDACi can modulate cellular responses to other cytotoxic modalities including ionizing and ultraviolet radiation and chemotherapeutic drugs (Karagiannis and El-Osta, 2006;Hajji et al, 2008). Many mechanisms have been proposed to explain the action of various HDACi, yet little is understood regarding how distinct HDACi can yield similar cellular effects seemingly regardless of structure and specificity.…”

Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential?

“…Histone deacetylase inhibitors can act as radiosensitisers (Karagiannis and El-Osta, 2006). For example, in NSCLC cells, synergism has been demonstrated between HDIs and irradiation for induction of apoptosis and inhibition of clonogenic survival and confirmed in in vivo tumour studies.…”