Abstract
Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers. However, the mechanisms of action are not well understood, and whether they could sensitize multiple myeloma (MM) to radiation therapy is unclear. In this study, we show that suberoylanilide hydroxamic acid (SAHA) at low concentrations has minimal cytotoxic effects, yet can significantly increase radiosensitivity of MM cells. SAHA seems to block RAD51 protein response to ionizing radiation, consistent with an inhibitory effect on the formation of RAD51 focus in irradiated MM cells. These effects of SAHA on RAD51 focus are independent of cell-cycle distribution changes. Furthermore, we show that SAHA selectively inhibits the homology-directed repair (HDR) pathway. The results of this study suggest that SAHA, a recently approved HDI in clinical trials for malignancies, at lower concentrations may act as a radiosensitizer via disruption of the RAD51-dependent HDR pathway.
Highlights
Multiple myeloma (MM) is an incurable plasma cell malignancy that accounts for about 1% of human cancers [1]
We show that suberoylanilide hydroxamic acid (SAHA) at low, minimally cytotoxic doses enhances radiosensitivity of MM cells in vitro, with a novel mechanism involving the inhibition of the homology-directed repair (HDR) pathway of chromosomal breaks
To test whether the observed effects of SAHA on RAD51 protein would affect the IRinduced recruitment of RAD51 to double-strand breaks (DSB) site, we evaluated the formation of nuclear cofoci of RAD51/g-H2A.X by immunofluorescence staining in irradiated MM cells
Summary
Multiple myeloma (MM) is an incurable plasma cell malignancy that accounts for about 1% of human cancers [1]. Standard systemic treatment has utilized alkylating agents, anthracyclines, steroids, antiangiogenics agents, proteasome inhibitors, and hematopoietic cell transplantation. Most myeloma patients initially respond to such approaches, median survival is approximately 4 years because of the refractory and/or relapsed disease [2]. Challenging are patients with progressive disease after first-line therapies [3]. These patients are often considered for hematopoietic cell transplantation (HCT). Total body irradiation (TBI) containing conditioning HCT regimens are difficult to tolerate given the fact that MM patients are older and the regimens are often combined with chemotherapy agents such as melphalan. Total marrow irradiation (TMI) delivery using large field image guided intensity
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