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Original Articles
In Vitro and In Vivo Radiosensitizing Effect of Valproic Acid on Fractionated Irradiation
Eui Kyu Chie, Jin Hee Shin, Jin Ho Kim, Hak Jae Kim, In Ah Kim, Il Han Kim
Cancer Res Treat. 2015;47(3):527-533.   Published online November 24, 2014
DOI: https://doi.org/10.4143/crt.2014.026
AbstractAbstract PDFPubReaderePub
Purpose
This study was conducted in order to validate the radiosensitization effect of valproic acid, a biologically available histone deacetylase inhibitor, for fractionated radiation.
Materials and Methods
Radiosensitization effect of valproic acid was tested for the A549 cell line and U87MG cell line in vitro. Fractionated irradiation of 12 Gy in four fractions was administered on D2-5 with valproic acid, 150 mg/Kg, ip, bid for six consecutive days (D1-6) to A549 and U87MG tumors implanted in BALB/c-nude mice. A growth delay curve was formulated.
Results
Radiosensitization effect of valproic acid was found for both cell lines; A549 at 1.5 mM and 3.0 mM concentration and U87MG at 3.0 mM concentration. In growth delay analysis, a statistically significant radiosensitization effect was observed for both tumors (p < 0.001 for both tumors). Difference for change in slope for control and valproic acid versus radiotherapy and radiotherapy plus valproic acid showed borderline significance for the U87MG cell line (p=0.065), indicating beyond additive effect, whereas this difference was statistically insignificant for A549 tumor (p=0.951), indicating additive effect.
Conclusion

Results
of this study indicate that a radiosensitizing effect for fractionated radiotherapy of valproic acid for A549 and U87MG tumors in vivo is evident and that it may be more than additive for U87MG tumors. Further exploitation of histone deacetylase inhibitors in clinical trials is warranted.

Citations

Citations to this article as recorded by  
  • Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study
    Peng-Yi Lee, Yu-Ting Wei, Kun-San Clifford Chao, Chin-Nan Chu, Wen-Hui Chung, Ti-Hao Wang*
    Journal of Cancer Research and Therapeutics.2024; 20(2): 555.     CrossRef
  • Valproic acid as a radio-sensitizer in glioma: A systematic review and meta-analysis
    Jessica K Sullivan, Paul P Fahey, Kinglsey E Agho, Simon P Hurley, Zhihui Feng, Richard O Day, David Lim
    Neuro-Oncology Practice.2023; 10(1): 13.     CrossRef
  • The function of histone methylation and acetylation regulators in GBM pathophysiology
    Colin McCornack, Timothy Woodiwiss, Angela Hardi, Hiroko Yano, Albert H. Kim
    Frontiers in Oncology.2023;[Epub]     CrossRef
  • Antitumor Activity of Non-thermal Atmospheric Pressure Plasma and Synergistic Effects of Hyperthermia
    TETSUO ADACHI
    Thermal Medicine.2022; 38(1): 1.     CrossRef
  • Epigenetic-Like Stimulation of Receptor Expression in SSTR2 Transfected HEK293 Cells as a New Therapeutic Strategy
    Joerg Kotzerke, Dorothee Buesser, Anne Naumann, Roswitha Runge, Lisa Huebinger, Andrea Kliewer, Robert Freudenberg, Claudia Brogsitter
    Cancers.2022; 14(10): 2513.     CrossRef
  • Molecular Mechanisms Underlying Cellular Responses to the Loading of Non-thermal Atmospheric Pressure Plasma-activated Solutions
    Tetsuo Adachi
    YAKUGAKU ZASSHI.2021; 141(10): 1185.     CrossRef
  • Ability of plasma-activated acetated Ringer’s solution to induce A549 cell injury is enhanced by a pre-treatment with histone deacetylase inhibitors
    Tetsuo Adachi, Yumiko Matsuda, Rika Ishii, Tetsuro Kamiya, Hirokazu Hara
    Journal of Clinical Biochemistry and Nutrition.2020; 67(3): 232.     CrossRef
  • Effect of valproic acid on overall survival in patients with high-grade gliomas undergoing temozolomide
    Yu-Jen Kuo, Yao-Hsu Yang, I-Yun Lee, Pau-Chung Chen, Jen-Tsung Yang, Ting-Chung Wang, Martin Hsiu-Chu Lin, Wei-Hsun Yang, Chun-Yu Cheng, Kuo-Tai Chen, Wei-Chao Huang, Ming-Hsueh Lee
    Medicine.2020; 99(28): e21147.     CrossRef
  • Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead
    Rashmi R. Shah, Peter D. Stonier
    Journal of Clinical Pharmacy and Therapeutics.2019; 44(1): 6.     CrossRef
  • Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation
    Jeong Il Yu, Changhoon Choi, Sung-Won Shin, Arang Son, Ga-Haeng Lee, Shin-Yeong Kim, Hee Chul Park
    Scientific Reports.2017;[Epub]     CrossRef
  • Histone deacetylase inhibitors stimulate the susceptibility of A549 cells to a plasma-activated medium treatment
    Tetsuo Adachi, Ayame Kano, Saho Nonomura, Tetsuro Kamiya, Hirokazu Hara
    Archives of Biochemistry and Biophysics.2016; 606: 120.     CrossRef
  • Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma
    Caroline Happold, Thierry Gorlia, Olivier Chinot, Mark R. Gilbert, L. Burt Nabors, Wolfgang Wick, Stephanie L. Pugh, Monika Hegi, Timothy Cloughesy, Patrick Roth, David A. Reardon, James R. Perry, Minesh P. Mehta, Roger Stupp, Michael Weller
    Journal of Clinical Oncology.2016; 34(7): 731.     CrossRef
  • 11,642 View
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  • 15 Web of Science
  • 12 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
AbstractAbstract PDFPubReaderePub
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
  • 12,619 View
  • 47 Download
  • 6 Web of Science
  • 8 Crossref
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Enhancement of Radiation Effects by Flavopiridol in Uterine Cervix Cancer Cells
Suzy Kim, Hong-Gyun Wu, Jin Hee Shin, Hye Jin Park, In Ah Kim, Il Han Kim
Cancer Res Treat. 2005;37(3):191-195.   Published online June 30, 2005
DOI: https://doi.org/10.4143/crt.2005.37.3.191
AbstractAbstract PDFPubReaderePub
Purpose

To determine the effects of combinations of radiation and flavopiridol, an inhibitor of cyclin-dependent kinases and global transcription, in a human uterine cervix cancer cell line.

Materials and Methods

Human uterine cervix cancer cells (HeLa), cultured to the mid-log phase, were exposed to X-rays, flavopiridol, and combinations of X-rays and flavopiridol in various sequences. The end point in this study was the clonogenic survival, which was measured via clonogenic assays. In order to determine the intrinsic cytotoxicity of flavopiridol, 0, 5, 12.5, 25, 37.5, 50 and 100 nM of flavopiridol were added to cell culture media. In the combination treatment, four different schedules of flavopiridol and irradiation combinations were tested: treatment of flavopiridol for 24 hours followed by irradiation, simultaneous administration of flavopiridol and irradiation, and irradiation followed by flavopiridol (for 24 hours) at intervals of 6 and 24 hours. The fraction of cells surviving after the combination treatment with 2 Gy of radiation (SF2) was compared with that of the fraction of cells surviving after treatment with irradiation alone.

Results

The cytotoxicity of flavopiridol was found to be dose-dependent, with an IC50 of 80 nM. No cytotoxic enhancements were observed when flavopiridol and radiation were administered simultaneously. Flavopiridol, administered either 24 hours before or 6 hours after irradiation, exerted no sensitizing effects on the cells. Only one protocol resulted in a radiosensitizing effect: the administration of flavopiridol 24 hours after irradiation.

Conclusion

Flavopiridol enhanced the effects of radiation on a uterine cervix cancer cell line in vitro, and this enhancement was both sequence- and time-dependent.

Citations

Citations to this article as recorded by  
  • Flavopiridol: a promising cyclin-dependent kinase inhibitor in cancer treatment
    Uttam Singh Baghel, Priyanka Kriplani, Neelam M. Patel, Manpreet Kaur, Kapil Sharma, Monika Meghani, Abhay Sharma, Deeksha Singh, Bhawani Singh, William N. Setzer, Javad Sharifi-Rad, Daniela Calina
    Naunyn-Schmiedeberg's Archives of Pharmacology.2024;[Epub]     CrossRef
  • BAIRDA: a novel in vitro setup to quantify radiobiological parameters for cervical cancer brachytherapy dose estimations
    Braden Chow, Brad Warkentin, Kareena Nanda, Sunita Ghosh, Fleur Huang, Armin M Gamper, Geetha Menon
    Physics in Medicine & Biology.2022; 67(4): 045012.     CrossRef
  • Nutraceutical Compounds as Sensitizers for Cancer Treatment in Radiation Therapy
    Marco Calvaruso, Gaia Pucci, Rosa Musso, Valentina Bravatà, Francesco P. Cammarata, Giorgio Russo, Giusi I. Forte, Luigi Minafra
    International Journal of Molecular Sciences.2019; 20(21): 5267.     CrossRef
  • Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor
    Young Eun Lee, Seung Ah Choi, Pil Ae Kwack, Hak Jae Kim, Il Han Kim, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Sung-Hye Park, Kyung Duk Park, Do Won Hwang, Kyeung Min Joo, Seung-Ki Kim
    Neuro-Oncology.2017; 19(8): 1079.     CrossRef
  • Interaction of ω-3 polyunsaturated fatty acids with radiation therapy in two different colorectal cancer cell lines
    Fang Cai, Olivier Sorg, Virginie Granci, Elena Lecumberri, Raymond Miralbell, Yves M. Dupertuis, Claude Pichard
    Clinical Nutrition.2014; 33(1): 164.     CrossRef
  • Antitumor Effects of Flavopiridol on Human Uterine Leiomyoma In Vitro and in a Xenograft Model
    Hyun-Gyo Lee, Jong-Woo Baek, So-Jin Shin, Sang-Hoon Kwon, Soon-Do Cha, Won-Jin Park, Rosa Chung, Eun-Som Choi, Gun-Ho Lee, Chi-Heum Cho
    Reproductive Sciences.2014; 21(9): 1153.     CrossRef
  • In VitroRadiosensitization of Flavopiridol Did Not Translated intoIn VivoRadiosensitization
    Suzy Kim
    The Journal of the Korean Society for Therapeutic Radiology and Oncology.2011; 29(2): 83.     CrossRef
  • Gold Nanoparticles as Radiation Sensitizers in Cancer Therapy
    Devika B. Chithrani, Salomeh Jelveh, Farid Jalali, Monique van Prooijen, Christine Allen, Robert G. Bristow, Richard P. Hill, David A. Jaffray
    Radiation Research.2010; 173(6): 719.     CrossRef
  • 9,295 View
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  • 8 Crossref
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A Histone Deacetylase Inhibitor, Trichostatin A, Enhances Radiosensitivity by Abrogating G2/M Arrest in Human Carcinoma Cells
In Ah Kim, Jin Ho Kim, Jin Hee Shin, Il Han Kim, Jae Sung Kim, Hong-Gyun Wu, Eui Kyu Chie, Yong Ho Kim, Bo-Kyung Kim, Semie Hong, Seok Won Park, Sung Whan Ha, Charn Il Park
Cancer Res Treat. 2005;37(2):122-128.   Published online April 30, 2005
DOI: https://doi.org/10.4143/crt.2005.37.2.122
AbstractAbstract PDFPubReaderePub
Purpose

Histone deacetylase inhibitors (HDIs) are emerging as potentially useful components in anticancer therapy. In this study, we tried to confirm the radiosensitizing effect of trichostatin A (TSA) on a panel of human carcinoma cell lines and elucidate its mechanism of interaction.

Materials and Methods

A549, HeLa and Caski cells were exposed to TSA for 18 hr prior to irradiation, and the cell survival then measured using a clonogenic assay. Western blot and flow cytometric analyses, for histone acetylation, and cell cycle and apoptosis, respectively, were also performed.

Results

TSA increased the acetylation of histone H3. The pretreatment of TSA consistently radiosensitized all three cell lines. The SF2 (surviving fraction at 2 Gy) of TSA-treated cells was significantly lower than that of mock treated cells. The SER (sensitizer enhancement ratio) increased in all 3 cell lines, in concentration dependent manners. The TSA treated cells showed abrogation of radiation-induced G2/M arrest, in a concentration dependent manner.

Conclusion

The pretreatment of TSA enhanced the radiosensitivity of a panel of human carcinoma cells, which was attributed, in part, to the abrogation of radiation-induced G2/M arrest.

Citations

Citations to this article as recorded by  
  • Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer
    Yijun Xie, Di Xiao, Duo Li, Mei Peng, Wei Peng, Huaxin Duan, Xiaoping Yang
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • Radiosensitizing effect of dendrosomal nanoformulation of curcumin on cancer cells
    Tahereh Jalali Varnamkhasti, Meisam Jafarzadeh, Majid Sadeghizadeh, Mahdi Aghili
    Pharmacological Reports.2022; 74(4): 718.     CrossRef
  • Pharmacological Properties of Trichostatin A, Focusing on the Anticancer Potential: A Comprehensive Review
    Abdelhakim Bouyahya, Nasreddine El Omari, Mohamed Bakha, Tarik Aanniz, Naoual El Menyiy, Naoufal El Hachlafi, Aicha El Baaboua, Mohamed El-Shazly, Mohammed Merae Alshahrani, Ahmed Abdullah Al Awadh, Learn-Han Lee, Taoufiq Benali, Mohammad S. Mubarak
    Pharmaceuticals.2022; 15(10): 1235.     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
  • Targeted Therapeutic Strategies for Triple-Negative Breast Cancer
    Ying Li, Zhijun Zhan, Xuemin Yin, Shujun Fu, Xiyun Deng
    Frontiers in Oncology.2021;[Epub]     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
  • Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53
    Manuela Terranova-Barberio, Biagio Pecori, Maria Serena Roca, Serena Imbimbo, Francesca Bruzzese, Alessandra Leone, Paolo Muto, Paolo Delrio, Antonio Avallone, Alfredo Budillon, Elena Di Gennaro
    Journal of Experimental & Clinical Cancer Research.2017;[Epub]     CrossRef
  • Histone Acetylation Induced Transformation of B-DNA to Z-DNA in Cells Probed through FT-IR Spectroscopy
    Fengqiu Zhang, Qing Huang, Jingwen Yan, Zhu Chen
    Analytical Chemistry.2016; 88(8): 4179.     CrossRef
  • Cell-based multi-substrate assay coupled to UHPLC-ESI-MS/MS for a quick identification of class-specific HDAC inhibitors
    Vincent Zwick, Claudia Simões-Pires, Muriel Cuendet
    Journal of Enzyme Inhibition and Medicinal Chemistry.2016; 31(sup1): 209.     CrossRef
  • Assessment of the Effect of Trichostatin A on HeLa Cells through FT-IR Spectroscopy
    Fengqiu Zhang, Qing Huang, Jingwen Yan, Xin Zhang, Jianxin Li
    Analytical Chemistry.2015; 87(4): 2511.     CrossRef
  • Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells
    Ahrum Min, Seock-Ah Im, Debora Keunyoung Kim, Sang-Hyun Song, Hee-Jun Kim, Kyung-Hun Lee, Tae-Yong Kim, Sae-Won Han, Do-Youn Oh, Tae-You Kim, Mark J O’Connor, Yung-Jue Bang
    Breast Cancer Research.2015;[Epub]     CrossRef
  • CD44 is a biomarker associated with human prostate cancer radiation sensitivity
    WeiWei Xiao, Peter H. Graham, Carl A. Power, Jingli Hao, John H. Kearsley, Yong Li
    Clinical & Experimental Metastasis.2012; 29(1): 1.     CrossRef
  • Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells
    Han Sang Kim, Sang Cheol Kim, Sun Jeong Kim, Chan Hee Park, Hei-Cheul Jeung, Yong Bae Kim, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha
    BMC Genomics.2012;[Epub]     CrossRef
  • In vivoRadiosensitization Effect of HDAC Inhibitor, SK-7041 on RIF-1 Cell Line
    Eui Kyu Chie, Jin Hee Shin, In Ah Kim, Il Han Kim
    The Journal of the Korean Society for Therapeutic Radiology and Oncology.2010; 28(4): 219.     CrossRef
  • Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: Potential role of histone deacetylase 6
    In Ah Kim, Mina No, Jang Mi Lee, Jin Hee Shin, Jee Sun Oh, Eun Jung Choi, Il Han Kim, Peter Atadja, Eric J. Bernhard
    Radiotherapy and Oncology.2009; 92(1): 125.     CrossRef
  • Histone Deacetylase Inhibitor–Mediated Radiosensitization of Human Cancer Cells: Class Differences and the Potential Influence of p53
    In Ah Kim, Jin Hee Shin, Il Han Kim, Jin Ho Kim, Jae Sung Kim, Hong Gyun Wu, Eui Kyu Chie, Sung Whan Ha, Charn Il Park, Gary D. Kao
    Clinical Cancer Research.2006; 12(3): 940.     CrossRef
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