Evaluation of Histone Deacetylase Inhibitors as Radiosensitizers for Proton and Light Ion Radiotherapy

Johnson, Alicia M.; Bennett, Paula V.; Sanidad, Katherine Z.; Hoang, Anthony; Jardine, James H.; Keszenman, Deborah J.; Wilson, Paul F.

doi:10.3389/fonc.2021.735940

Evaluation of Histone Deacetylase Inhibitors as Radiosensitizers for Proton and Light Ion Radiotherapy

Journal Article · Thu Aug 26 00:00:00 EDT 2021 · Frontiers in Oncology

DOI:https://doi.org/10.3389/fonc.2021.735940· OSTI ID:1842813

Johnson, Alicia M. ^[1]; Bennett, Paula V. ^[1]; Sanidad, Katherine Z. ^[1]; Hoang, Anthony ^[1]; Jardine, James H. ^[1]; Keszenman, Deborah J. ^[2]; Wilson, Paul F. ^[3]

Brookhaven National Lab. (BNL), Upton, NY (United States)
Brookhaven National Lab. (BNL), Upton, NY (United States); Univ. de la Republica (UdelaR), Salto (Uruguay). Centro Universitario Regional Litorl Norte, Lab. de Radiobiologia Medica y Ambiental
Brookhaven National Lab. (BNL), Upton, NY (United States); Univ. of California Davis, Sacramento, CA (United States)

Significant opportunities remain for pharmacologically enhancing the clinical effectiveness of proton and carbon ion-based radiotherapies to achieve both tumor cell radiosensitization and normal tissue radioprotection. We investigated whether pretreatment with the hydroxamate-based histone deacetylase inhibitors (HDACi) SAHA (vorinostat), M344, and PTACH impacts radiation-induced DNA double-strand break (DSB) induction and repair, cell killing, and transformation (acquisition of anchorage-independent growth in soft agar) in human normal and tumor cell lines following gamma ray and light ion irradiation. Treatment of normal NFF28 primary fibroblasts and U2OS osteosarcoma, A549 lung carcinoma, and U87MG glioma cells with 5–10 µM HDACi concentrations 18 h prior to cesium-137 gamma irradiation resulted in radiosensitization measured by clonogenic survival assays and increased levels of colocalized gamma-H2AX/53BP1 foci induction. We similarly tested these HDACi following irradiation with 200 MeV protons, 290 MeV/n carbon ions, and 350 MeV/n oxygen ions delivered in the Bragg plateau region. Unlike uniform gamma ray radiosensitization, effects of HDACi pretreatment were unexpectedly cell type and ion species-dependent with C-12 and O-16 ion irradiations showing enhanced G0/G1-phase fibroblast survival (radioprotection) and in some cases reduced or absent tumor cell radiosensitization. DSB-associated foci levels were similar for proton-irradiated DMSO control and SAHA-treated fibroblast cultures, while lower levels of induced foci were observed in SAHA-pretreated C-12 ion-irradiated fibroblasts. Fibroblast transformation frequencies measured for all radiation types were generally LET-dependent and lowest following proton irradiation; however, both gamma and proton exposures showed hyperlinear transformation induction at low doses (≤25 cGy). HDACi pretreatments led to overall lower transformation frequencies at low doses for all radiation types except O-16 ions but generally led to higher transformation frequencies at higher doses (>50 cGy). The results of these in vitro studies cast doubt on the clinical efficacy of using HDACi as radiosensitizers for light ion-based hadron radiotherapy given the mixed results on their radiosensitization effectiveness and related possibility of increased second cancer induction.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: National Aeronautics and Space Administration (NASA); USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: AC02-98CH10886; SC0012704

OSTI ID:: 1842813

Report Number(s):: BNL--222689-2022-JAAM

Journal Information:: Frontiers in Oncology, Journal Name: Frontiers in Oncology Vol. 11; ISSN 2234-943X

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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ionizing
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Evaluation of Histone Deacetylase Inhibitors as Radiosensitizers for Proton and Light Ion Radiotherapy

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