Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Radiation Oncology
Published in: Radiation Oncology 1/2011

Open Access 01-12-2011 | Research

Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

Authors: Pei-Ming Chu, Shih-Hwa Chiou, Tsann-Long Su, Yi-Jang Lee, Li-Hsin Chen, Yi-Wei Chen, Sang-Hue Yen, Ming-Teh Chen, Ming-Hsiung Chen, Yang-Hsin Shih, Pang-Hsien Tu, Hsin-I Ma

Published in: Radiation Oncology | Issue 1/2011

Login to get access

Abstract

Background

1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy.

Methods

The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method.

Results

BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly.

Conclusions

These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells.
Appendix
Available only for authorised users
Literature
1.
Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, et al.: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980,303(23):1323-1329. 10.1056/NEJM198012043032303CrossRefPubMed
2.
Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, et al.: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002,20(5):1375-1382. 10.1200/JCO.20.5.1375CrossRefPubMed
3.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005,352(10):987-996. 10.1056/NEJMoa043330CrossRefPubMed
4.
Wadhwa PD, Zielske SP, Roth JC, Ballas CB, Bowman JE, Gerson SL: Cancer gene therapy: scientific basis. Annu Rev Med 2002, 53: 437-452. 10.1146/annurev.med.53.082901.104039CrossRefPubMed
5.
Grando SA, Kawashima K, Wessler I: Introduction: the non-neuronal cholinergic system in humans. Life Sci 2003,72(18-19):2009-2012. 10.1016/S0024-3205(03)00063-8CrossRefPubMed
6.
Maze R, Carney JP, Kelley MR, Glassner BJ, Williams DA, Samson L: Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent. Proc Natl Acad Sci USA 1996,93(1):206-210. 10.1073/pnas.93.1.206PubMedCentralCrossRefPubMed
7.
Gravatt GL, Baguley BC, Wilson WR, Denny WA: DNA-directed alkylating agents. 6. Synthesis and antitumor activity of DNA minor groove-targeted aniline mustard analogues of pibenzimol (Hoechst 33258). J Med Chem 1994,37(25):4338-4345. 10.1021/jm00051a010CrossRefPubMed
8.
Gourdie TA, Valu KK, Gravatt GL, Boritzki TJ, Baguley BC, Wakelin LP, Wilson WR, Woodgate PD, Denny WA: DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard. J Med Chem 1990,33(4):1177-1186. 10.1021/jm00166a015CrossRefPubMed
9.
Bacherikov VA, Chou TC, Dong HJ, Zhang X, Chen CH, Lin YW, Tsai TJ, Lee RZ, Liu LF, Su TL: Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: synthesis and biological activity. Bioorg Med Chem 2005,13(12):3993-4006. 10.1016/j.bmc.2005.03.057CrossRefPubMed
10.
Su TL, Lin YW, Chou TC, Zhang X, Bacherikov VA, Chen CH, Liu LF, Tsai TJ: Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity. J Med Chem 2006,49(12):3710-3718. 10.1021/jm060197rCrossRefPubMed
11.
Su TL: Development of DNA topoisomerase II-mediated anticancer agents, 3-(9-acridinylamino)-5-hydroxymethylanilines (AHMAs) and related compounds. Curr Med Chem 2002,9(18):1677-1688.PubMed
12.
Lee CH, Chou TC, Su TL, Yu J, Shao LE, Yu AL: BO-0742, a derivative of AHMA and N-mustard, has selective toxicity to drug sensitive and drug resistant leukemia cells and solid tumors. Cancer Lett 2009,276(2):204-211. 10.1016/j.canlet.2008.11.006CrossRefPubMed
13.
Kapuriya N, Kapuriya K, Dong H, Zhang X, Chou TC, Chen YT, Lee TC, Lee WC, Tsai TH, Naliapara Y, et al.: Novel DNA-directed alkylating agents: design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker. Bioorg Med Chem 2009,17(3):1264-1275. 10.1016/j.bmc.2008.12.022CrossRefPubMed
14.
Kapuriya N, Kapuriya K, Zhang X, Chou TC, Kakadiya R, Wu YT, Tsai TH, Chen YT, Lee TC, Shah A, et al.: Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage. Bioorg Med Chem 2008,16(10):5413-5423. 10.1016/j.bmc.2008.04.024CrossRefPubMed
15.
Kim JH, Shin JH, Kim IH: Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor. Int J Radiat Oncol Biol Phys 2004,59(4):1174-1180. 10.1016/j.ijrobp.2004.03.001CrossRefPubMed
16.
Camphausen K, Brady KJ, Burgan WE, Cerra MA, Russell JS, Bull EE, Tofilon PJ: Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of gammaH2AX foci. Mol Cancer Ther 2004,3(4):409-416.PubMed
17.
McCord AM, Jamal M, Williams ES, Camphausen K, Tofilon PJ: CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res 2009,15(16):5145-5153. 10.1158/1078-0432.CCR-09-0263CrossRefPubMed
18.
Dote H, Cerna D, Burgan WE, Carter DJ, Cerra MA, Hollingshead MG, Camphausen K, Tofilon PJ: Enhancement of in vitro and in vivo tumor cell radiosensitivity by the DNA methylation inhibitor zebularine. Clin Cancer Res 2005,11(12):4571-4579. 10.1158/1078-0432.CCR-05-0050CrossRefPubMed
19.
Barker CA, Burgan WE, Carter DJ, Cerna D, Gius D, Hollingshead MG, Camphausen K, Tofilon PJ: In vitro and in vivo radiosensitization induced by the ribonucleotide reductase inhibitor Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone). Clin Cancer Res 2006,12(9):2912-2918. 10.1158/1078-0432.CCR-05-2860CrossRefPubMed
20.
Russell JS, Burgan W, Oswald KA, Camphausen K, Tofilon PJ: Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17- demethoxygeldanamycin: a multitarget approach to radiosensitization. Clin Cancer Res 2003,9(10 Pt 1):3749-3755.PubMed
21.
Geldof AA, Slotman BJ: Radiosensitizing effect of cisplatin in prostate cancer cell lines. Cancer Lett 1996,101(2):233-239. 10.1016/0304-3835(96)04140-7CrossRefPubMed
22.
Pawlik TM, Keyomarsi K: Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 2004,59(4):928-942. 10.1016/j.ijrobp.2004.03.005CrossRefPubMed
23.
Sinclair WK, Morton RA: X-ray sensitivity during the cell generation cycle of cultured Chinese hamster cells. Radiat Res 1966,29(3):450-474. 10.2307/3572025CrossRefPubMed
24.
Pilch DR, Sedelnikova OA, Redon C, Celeste A, Nussenzweig A, Bonner WM: Characteristics of gamma-H2AX foci at DNA double-strand breaks sites. Biochem Cell Biol 2003,81(3):123-129. 10.1139/o03-042CrossRefPubMed
25.
Chakravarti A, Erkkinen MG, Nestler U, Stupp R, Mehta M, Aldape K, Gilbert MR, Black PM, Loeffler JS: Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res 2006,12(15):4738-4746. 10.1158/1078-0432.CCR-06-0596CrossRefPubMed
26.
Kil WJ, Cerna D, Burgan WE, Beam K, Carter D, Steeg PS, Tofilon PJ, Camphausen K: In vitro and in vivo radiosensitization induced by the DNA methylating agent temozolomide. Clin Cancer Res 2008,14(3):931-938. 10.1158/1078-0432.CCR-07-1856CrossRefPubMed
27.
Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S: Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 2004,11(4):448-457. 10.1038/sj.cdd.4401359CrossRefPubMed
28.
Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, et al.: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000,83(5):588-593. 10.1054/bjoc.2000.1316PubMedCentralCrossRefPubMed
29.
Tomasz M, Palom Y: The mitomycin bioreductive antitumor agents: cross-linking and alkylation of DNA as the molecular basis of their activity. Pharmacol Ther 1997,76(1-3):73-87. 10.1016/S0163-7258(97)00088-0CrossRefPubMed
30.
Panasci L, Xu ZY, Bello V, Aloyz R: The role of DNA repair in nitrogen mustard drug resistance. Anticancer Drugs 2002,13(3):211-220. 10.1097/00001813-200203000-00002CrossRefPubMed
31.
Sorensen CS, Hansen LT, Dziegielewski J, Syljuasen RG, Lundin C, Bartek J, Helleday T: The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol 2005,7(2):195-201. 10.1038/ncb1212CrossRefPubMed
32.
Kakadiya R, Dong H, Lee PC, Kapuriya N, Zhang X, Chou TC, Lee TC, Kapuriya K, Shah A, Su TL: Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes. Bioorg Med Chem 2009,17(15):5614-5626. 10.1016/j.bmc.2009.06.018CrossRefPubMed
33.
Kakadiya R, Dong H, Kumar A, Narsinh D, Zhang X, Chou TC, Lee TC, Shah A, Su TL: Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker. Bioorg Med Chem 2010,18(6):2285-2299. 10.1016/j.bmc.2010.01.061CrossRefPubMed
34.
Shrivastav M, De Haro LP, Nickoloff JA: Regulation of DNA double-strand break repair pathway choice. Cell Res 2008,18(1):134-147. 10.1038/cr.2007.111CrossRefPubMed
35.
Zou H, Zhao S, Zhang J, Lv G, Zhang X, Yu H, Wang H, Wang L: Enhanced radiation-induced cytotoxic effect by 2-ME in glioma cells is mediated by induction of cell cycle arrest and DNA damage via activation of ATM pathways. Brain Res 2007, 1185: 231-238. 10.1016/j.brainres.2007.07.092CrossRefPubMed
36.
Jin C, Wu H, Liu J, Bai L, Guo G: The effect of paclitaxel-loaded nanoparticles with radiation on hypoxic MCF-7 cells. J Clin Pharm Ther 2007,32(1):41-47. 10.1111/j.1365-2710.2007.00796.xCrossRefPubMed
37.
Furuta Y, Hunter N, Barkley T Jr, Hall E, Milas L: Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res 1988,48(11):3008-3013.PubMed
38.
Samuel T, Weber HO, Funk JO: Linking DNA damage to cell cycle checkpoints. Cell Cycle 2002,1(3):162-168. 10.4161/cc.1.3.118CrossRefPubMed
39.
Herzinger T, Funk JO, Hillmer K, Eick D, Wolf DA, Kind P: Ultraviolet B irradiation-induced G2 cell cycle arrest in human keratinocytes by inhibitory phosphorylation of the cdc2 cell cycle kinase. Oncogene 1995,11(10):2151-2156.PubMed
40.
Kastan MB, Lim DS: The many substrates and functions of ATM. Nat Rev Mol Cell Biol 2000,1(3):179-186. 10.1038/35043058CrossRefPubMed
41.
Collis SJ, Swartz MJ, Nelson WG, DeWeese TL: Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res 2003,63(7):1550-1554.PubMed
42.
Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM: DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998,273(10):5858-5868. 10.1074/jbc.273.10.5858CrossRefPubMed
43.
Sedelnikova OA, Rogakou EP, Panyutin IG, Bonner WM: Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. Radiat Res 2002,158(4):486-492. 10.1667/0033-7587(2002)158[0486:QDOIID]2.0.CO;2CrossRefPubMed
44.
Olive PL, Banath JP: Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol Biol Phys 2004,58(2):331-335. 10.1016/j.ijrobp.2003.09.028CrossRefPubMed
45.
Nazarov IB, Smirnova AN, Krutilina RI, Svetlova MP, Solovjeva LV, Nikiforov AA, Oei SL, Zalenskaya IA, Yau PM, Bradbury EM, et al.: Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A. Radiat Res 2003,160(3):309-317. 10.1667/RR3043CrossRefPubMed
46.
Banath JP, Macphail SH, Olive PL: Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res 2004,64(19):7144-7149. 10.1158/0008-5472.CAN-04-1433CrossRefPubMed
47.
Bilsland E, Downs JA: Tails of histones in DNA double-strand break repair. Mutagenesis 2005,20(3):153-163. 10.1093/mutage/gei031CrossRefPubMed
48.
Lobrich M, Jeggo PA: Harmonising the response to DSBs: a new string in the ATM bow. DNA Repair (Amst) 2005,4(7):749-759. 10.1016/j.dnarep.2004.12.008CrossRef
49.
Mitchell JB, Choudhuri R, Fabre K, Sowers AL, Citrin D, Zabludoff SD, Cook JA: In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clin Cancer Res 2010,16(7):2076-2084. 10.1158/1078-0432.CCR-09-3277PubMedCentralCrossRefPubMed
50.
Lehmann BD, McCubrey JA, Terrian DM: Radiosensitization of Prostate Cancer by Priming the Wild-Type p53-Dependent Cellular Senescence Pathway. Cancer Biol Ther 2007,6(8):1165-1170.PubMedCentralCrossRefPubMed
51.
Fujiwara K, Iwado E, Mills GB, Sawaya R, Kondo S, Kondo Y: Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy. Int J Oncol 2007,31(4):753-760.PubMed
52.
Kim KW, Hwang M, Moretti L, Jaboin JJ, Cha YI, Lu B: Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 2008,4(5):659-668.PubMedCentralCrossRefPubMed
53.
Tsuboi Y, Kurimoto M, Nagai S, Hayakawa Y, Kamiyama H, Hayashi N, Kitajima I, Endo S: Induction of autophagic cell death and radiosensitization by the pharmacological inhibition of nuclear factor-kappa B activation in human glioma cell lines. J Neurosurg 2009,110(3):594-604. 10.3171/2008.8.JNS17648CrossRefPubMed
Metadata
Title
Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response
Authors
Pei-Ming Chu
Shih-Hwa Chiou
Tsann-Long Su
Yi-Jang Lee
Li-Hsin Chen
Yi-Wei Chen
Sang-Hue Yen
Ming-Teh Chen
Ming-Hsiung Chen
Yang-Hsin Shih
Pang-Hsien Tu
Hsin-I Ma
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2011
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/1748-717X-6-7

Other articles of this Issue 1/2011

Radiation Oncology 1/2011 Go to the issue

Research

Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy

Research

Targeting ανβ3 and ανβ5 inhibits photon-induced hypermigration of malignant glioma cells

Review

Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

Research

[18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes

Research

Inter-observer variability in contouring the penile bulb on CT images for prostate cancer treatment planning

Research

Gemcitabine/cisplatin versus 5-fluorouracil/mitomycin C chemoradiotherapy in locally advanced pancreatic cancer: a retrospective analysis of 93 patients