DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells

被引：36

作者：

Pont, Lotte M. E. Berghauser ^{[1
]}

Naipal, Kishan ^{[2
]}

Kloezeman, Jenneke J. ^{[1
]}

Venkatesan, Subramanian ^{[1
]}

van den Bent, Martin ^{[3
]}

van Gent, Dik C. ^{[2
]}

Dirven, Clemens M. F. ^{[1
]}

Kanaar, Roland ^{[2
]}

Lamfers, Martine L. M. ^{[1
]}

Leenstra, Sieger ^{[1
,4
]}

机构：

[1] Erasmus MC, Brain Tumor Ctr, Dept Neurosurg, NL-3015 CN Rotterdam, Netherlands

[2] Erasmus MC Canc Inst, Canc Genom Netherlands, Dept Radiat Oncol, Dept Genet, NL-3000 CA Rotterdam, Netherlands

[3] Erasmus MC Canc Inst, Brain Tumor Ctr, Dept Neurol Neurooncol, NL-3015 GE Rotterdam, Netherlands

[4] Elizabeth Med Hosp, Dept Neurosurg, Tilburg, Netherlands

来源：

CANCER LETTERS | 2015年 / 356卷 / 02期

关键词：

HDAC inhibitors; Glioblastoma; Radiation; Chek2; Bcl-XL; HISTONE DEACETYLASE INHIBITORS; SUBEROYLANILIDE HYDROXAMIC ACID; HUMAN TUMOR-CELLS; CANCER-CELLS; IONIZING-RADIATION; GAMMA-H2AX FOCI; VALPROIC ACID; EXPRESSION; REPAIR; RADIOTHERAPY;

D O I：

10.1016/j.canlet.2014.09.049

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

HDAC inhibitors have radiosensitizing effects in established cancer cell lines. This study was conducted to compare the efficacy of SAHA, LBH589, Valproic Acid (VPA), MS275 and Scriptaid in the patient-derived glioblastoma model. In more detail, SAHA and LBH589 were evaluated to determine predictors of response. Acetylated-histone-H3, gamma H2AX/53BP1, (p)Chek2/ATM, Bcl-2/Bcl-XL, p21(CIP1/WAF1) and caspase-3/7 were studied in relation to response. SAHA sensitized 50% of cultures, LBH589 45%, VPA and Scriptaid 40% and MS275 60%. Differences after treatment with SAHA/RTx or LBH589/RTx in a sensitive and resistant culture were increased acetylated-H3, caspase-3/7 and prolonged DNA damage repair gamma H2AX/53BP1 foci. pChek2 was found to be associated with both SAHA/RTx and LBH589/RTx response with a positive predictive value (PPV) of 90%. Bcl-XL had a PPV of 100% for LBH589/RTx response. Incubation with HDACi 24 and 48 hours pre-RTx resulted in the best efficacy of combination treatment. In conclusion a subset of patient-derived glioblastoma cultures were sensitive to HDACi/RTx. For SAHA and LBH589 responses were strongly associated with pChek2 and Bcl-XL, which warrant further clinical exploration. Additional information on responsiveness was obtained by DNA damage response markers and apoptosis related proteins. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

引用

页码：525 / 535

页数：11

共 39 条

[1] Serum-free culture success of glial tumors is related to specific molecular profiles and expression of extracellular matrixassociated gene modules [J].

Balvers, Rutger K. ;

Kleijn, Anne ;

Kloezeman, Jenneke J. ;

French, Pim J. ;

Kremer, Andreas ;

van den Bent, Martin J. ;

Dirven, Clemens M. F. ;

Leenstra, Sieger ;

Lamfers, Martine L. M. .

NEURO-ONCOLOGY, 2013, 15 (12) :1684-1695

[2] Anticancer activities of histone deacetylase inhibitors [J].

Bolden, Jessica E. ;

Peart, Melissa J. ;

Johnstone, Ricky W. .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (09) :769-784

[3] Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid [J].

Camphausen, K ;

Cerna, D ;

Scott, T ;

Sproull, M ;

Burgan, WE ;

Cerra, MA ;

Fine, H ;

Tofilon, PJ .

INTERNATIONAL JOURNAL OF CANCER, 2005, 114 (03) :380-386

[4] Enhanced radiation-induced cell killing and prolongation of γH2AX foci expression by the histone deacetylase inhibitor MS-275 [J].

Camphausen, K ;

Burgan, W ;

Cerra, M ;

Oswald, KA ;

Trepel, JB ;

Lee, MJ ;

Tofilon, PJ .

CANCER RESEARCH, 2004, 64 (01) :316-321

[5] DEVD-NucView488: a novel class of enzyme substrates for real-time detection of caspase-3 activity in live cells [J].

Cen, Hui ;

Mao, Fei ;

Aronchik, Ida ;

Fuentes, Rholinelle Joy ;

Firestone, Gary L. .

FASEB JOURNAL, 2008, 22 (07) :2243-2252

[6] Wip1 Directly Dephosphorylates Y-H2AX and Attenuates the DNA Damage Response [J].

Cha, Hyukjin ;

Lowe, Julie M. ;

Li, Henghong ;

Lee, Ji-Seon ;

Belova, Galina I. ;

Bulavin, Dmitry V. ;

Fornace, Albert J., Jr. .

CANCER RESEARCH, 2010, 70 (10) :4112-4122

[7] Suberoylanilide Hydroxamic Acid as a Radiosensitizer through Modulation of RAD51 Protein and Inhibition of Homology-Directed Repair in Multiple Myeloma [J].

Chen, Xufeng ;

Wong, Patty ;

Radany, Eric H. ;

Stark, Jeremy M. ;

Laulier, Corentin ;

Wong, Jeffrey Y. C. .

MOLECULAR CANCER RESEARCH, 2012, 10 (08) :1052-1064

[8] HDAC Inhibitor, Valproic Acid, Induces p53-Dependent Radiosensitization of Colon Cancer Cells [J].

Chen, Xufeng ;

Wong, Patty ;

Radany, Eric ;

Wong, Jeffrey Y. C. .

CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS, 2009, 24 (06) :689-699

[9] Modulation of radiation response by histone deacetylase inhibition [J].

Chinnaiyan, P ;

Vallabhaneni, G ;

Armstrong, E ;

Huang, SM ;

Harari, PM .

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2005, 62 (01) :223-229

[10] Postradiation sensitization of the histone deacetylase inhibitor valproic acid [J].

Chinnaiyan, Prakash ;

Cerna, David ;

Burgan, William E. ;

Beam, Katie ;

Williams, Eli S. ;

Camphausen, Kevin ;

Tofilon, Philip J. .

CLINICAL CANCER RESEARCH, 2008, 14 (17) :5410-5415

← 1 2 3 4 →