Abstract
Histone deacetylase inhibitors (HDIs) have shown promise as candidate radiosensitizer for many types of cancers. However, the mechanisms of action are not well understood, and whether they could have clinical impact on radiotherapy for leukemia is unclear. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) can increase radiosensitivity of acute myeloid leukemia (AML) cells through posttranslational modification of Rad51 protein responses and selective inhibition of the homology-directed repair (HDR) pathway. Our data also showed that AML cells with mutant, constitutively active FMS-like tyrosine kinase-3 (FLT3) were more radiation sensitive, caused by compromised non-homologous end joining (NHEJ) repair. Furthermore, SAHA-induced radiosensitization were enhanced in AML cells with expression of these FLT3 mutants. The results of this study suggest that SAHA, a recently approved HDI in clinical trials, may act as a candidate component for novel conditioning regimens to improve efficacy for AML patients undergoing radiotherapy and chemotherapy.
Highlights
Total body irradiation (TBI) continues to be important part of conditioning regimens for acute myelogenous leukemia (AML) patients undergoing hematopoietic cell transplantation (HCT)
Our results showed that the LD50's of suberoylanilide hydroxamic acid (SAHA) on tested AML cells ranged from 1.41 μM to 2.13 μM
We found that pretreatment with both 200 nM and 1 μM of SAHA resulted in remarkable radiosensitization in all AML cell lines tested (Figure 1C)
Summary
Total body irradiation (TBI) continues to be important part of conditioning regimens for acute myelogenous leukemia (AML) patients undergoing hematopoietic cell transplantation (HCT). Advanced technology using image-guided intensity modulated radiotherapy, referred as total marrow irradiation (TMI), allows delivering highly conformal dose distributions to large complex target shapes such as the bone/bone marrow, while simultaneously reducing dose to critical normal organs [3,4]. Using this approach, radiation sensitizers take on greater importance in the transplant setting, since dose deposition can be controlled and redistributed preferentially to marrow and away from normal organs, resulting in selective radiosensitization of marrow compared to normal tissues. The benefits of a radiosensitization strategy with even modest effects will be further amplified due to selective targeting of dose and radiosensitization to marrow and other user specified target structures
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