Cancer Research and Treatment

Original Articles

Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy: Erta Kalanxhi, Karianne Risberg, Imon S. Barua, Svein Dueland, Stein Waagene, Solveig Norheim Andersen, Solveig J. Pettersen, Jessica M. Lindvall, Kathrine Røe Redalen, Kjersti Flatmark, Anne Hansen Ree; Cancer Res Treat. 2017;49(2):374-386. Published online July 28, 2016; DOI: https://doi.org/10.4143/crt.2016.080

Purpose
When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser.
Materials and Methods
This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA.
Results
PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss.
Conclusion
The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

Citations

Citations to this article as recorded by

Effect of MicroRNA-210 on the Growth of Ovarian Cancer Cells and the Efficacy of Radiotherapy
Yinlong Zhao, Shirui Liu, Yu Wen, Lili Zhong
Gynecologic and Obstetric Investigation.2021; 86(1-2): 71. CrossRef
Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus
Félix G. Delgado, Paola Cárdenas, Jaime E. Castellanos
Diseases.2018; 6(3): 59. CrossRef
Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs
Silmara N. Andrade, Fernanda C. G. Evangelista, Diego Seckler, Deisielly R. Marques, Túlio R. Freitas, Renata R. Nunes, Júlia T. Oliveira, Rosy I. M. A. Ribeiro, Hélio B. Santos, Ralph G. Thomé, Alex G. Taranto, Fabio V. Santos, Gustavo H. R. Viana, Rossi
Medicinal Chemistry Research.2018; 27(11-12): 2397. CrossRef
Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity
Blaz Groselj, Jia-Ling Ruan, Helen Scott, Jessica Gorrill, Judith Nicholson, Jacqueline Kelly, Selvakumar Anbalagan, James Thompson, Michael R.L. Stratford, Sarah J. Jevons, Ester M. Hammond, Cheryl L. Scudamore, Martin Kerr, Anne E. Kiltie
Molecular Cancer Therapeutics.2018; 17(2): 381. CrossRef

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Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041: Jin Ho Kim, Il Han Kim, Jin Hee Shin, Hak Jae Kim, In Ah Kim; Cancer Res Treat. 2013;45(4):334-342. Published online December 31, 2013; DOI: https://doi.org/10.4143/crt.2013.45.4.334

Abstract PDF PubReader ePub

PURPOSE
This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation.
MATERIALS AND METHODS
The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution.
RESULTS
TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naive cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest.
CONCLUSION
TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.

Citations

Citations to this article as recorded by

Mechanistic Sequence of Histone Deacetylase Inhibitors and Radiation Treatment: An Overview
Elsie Neo Seane, Shankari Nair, Charlot Vandevoorde, Anna Joubert
Pharmaceuticals.2024; 17(5): 602. CrossRef
Investigation of geroprotective and radioprotective effects of berberine and trichostatin A on the model of Drosophila melanogaster
N. Ulyasheva, E. Proshkina, M. Shaposhnikov, A. Moskalev
Proceedings of the Komi Science Centre of the Ural Division of the Russian Academy of Sciences.2023; 0(6): 93. CrossRef
Low Dose of Trichostatin A Improves Radiation Resistance by Activating Akt/Nrf2-Dependent Antioxidation Pathway in Cancer Cells
Fengqiu Zhang, Changsheng Shao, Zhu Chen, Yalin Li, Xumiao Jing, Qing Huang
Radiation Research.2021;[Epub] CrossRef
Time-sequential change in immune-related gene expression after irradiation in glioblastoma: next-generation sequencing analysis
Yi-Jun Kim, Kwangsoo Kim, Soo Yeon Seo, Juyeon Yu, Il Han Kim, Hak Jae Kim, Chul-Kee Park, Kye Hwa Lee, Junjeong Choi, Myung Seon Song, Jin Ho Kim
Animal Cells and Systems.2021; 25(4): 245. CrossRef
Is level of acetylation directly correlated to radiation sensitivity of cancer cell?
Fengqiu Zhang, Zhu Chen, Changsheng Shao, Qing Huang
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis.2019; 813: 13. CrossRef
Disulfiram, a Re-positioned Aldehyde Dehydrogenase Inhibitor, Enhances Radiosensitivity of Human Glioblastoma Cells In Vitro
Hyeon Kang Koh, Soo Yeon Seo, Jin Ho Kim, Hak Jae Kim, Eui Kyu Chie, Seung-Ki Kim, Il Han Kim
Cancer Research and Treatment.2019; 51(2): 696. CrossRef
Psammaplin A-Modified Novel Radiosensitizers for Human Lung Cancer and Glioblastoma Cells
Chan Woo Wee, Jin Ho Kim, Hak Jae Kim, Hyun-Cheol Kang, Soo Youn Suh, Beom Soo Shin, Eunsook Ma, Il Han Kim
Journal of Radiation Protection and Research.2019; 44(1): 15. CrossRef
Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization
Jin Ho Kim, Sung Ho Moon, Mina No, Jae Jin Kim, Eun Jung Choi, Bong Jun Cho, Jae Sung Kim, Il Han Kim, In Ah Kim
Cancer Research and Treatment.2016; 48(3): 1130. CrossRef

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