Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival.
Animals
Antineoplastic Agents
/ administration & dosage
Bortezomib
/ administration & dosage
Brain Neoplasms
/ diagnostic imaging
Cell Line, Tumor
Drug Administration Schedule
Drug Resistance, Neoplasm
/ drug effects
Glioblastoma
/ diagnostic imaging
High-Throughput Nucleotide Sequencing
Humans
Kaplan-Meier Estimate
Methylation
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
O(6)-Methylguanine-DNA Methyltransferase
/ drug effects
Polymerase Chain Reaction
Promoter Regions, Genetic
RNA, Messenger
/ metabolism
Temozolomide
/ administration & dosage
Transcription Factor RelA
/ metabolism
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
26
04
2019
accepted:
25
07
2019
revised:
10
07
2019
pubmed:
16
8
2019
medline:
21
5
2020
entrez:
16
8
2019
Statut:
ppublish
Résumé
Resistance to temozolomide (TMZ) is due in part to enhanced DNA repair mediated by high expression of O Cell lines and patient GBM-derived cells were examined in vitro, and the latter also implanted orthotopically into NOD-SCID C.B.-Igh-1b/lcrTac-Prkdc mice to assess efficacy and tolerability of BTZ and TMZ combination therapy. MGMT promoter methylation was determined using pyrosequencing and PCR, protein signalling utilised western blotting while drug biodistribution was examined by LC-MS/MS. Statistical analysis utilised Analysis of variance and the Kaplan-Meier method. Pre-treatment with BTZ prior to temozolomide killed chemoresistant GBM cells with unmethylated MGMT promoter through MGMT mRNA and protein depletion in vitro without affecting methylation. Chymotryptic activity was abolished, processing of NFkB/p65 to activated forms was reduced and corresponded with low MGMT levels. BTZ crossed the blood-brain barrier, diminished proteasome activity and significantly prolonged animal survival. BTZ chemosensitized resistant GBM cells, and the schedule may be amenable for temozolomide refractory patients with unmethylated MGMT promoter.
Sections du résumé
BACKGROUND
Resistance to temozolomide (TMZ) is due in part to enhanced DNA repair mediated by high expression of O
METHODS
Cell lines and patient GBM-derived cells were examined in vitro, and the latter also implanted orthotopically into NOD-SCID C.B.-Igh-1b/lcrTac-Prkdc mice to assess efficacy and tolerability of BTZ and TMZ combination therapy. MGMT promoter methylation was determined using pyrosequencing and PCR, protein signalling utilised western blotting while drug biodistribution was examined by LC-MS/MS. Statistical analysis utilised Analysis of variance and the Kaplan-Meier method.
RESULTS
Pre-treatment with BTZ prior to temozolomide killed chemoresistant GBM cells with unmethylated MGMT promoter through MGMT mRNA and protein depletion in vitro without affecting methylation. Chymotryptic activity was abolished, processing of NFkB/p65 to activated forms was reduced and corresponded with low MGMT levels. BTZ crossed the blood-brain barrier, diminished proteasome activity and significantly prolonged animal survival.
CONCLUSION
BTZ chemosensitized resistant GBM cells, and the schedule may be amenable for temozolomide refractory patients with unmethylated MGMT promoter.
Identifiants
pubmed: 31413318
doi: 10.1038/s41416-019-0551-1
pii: 10.1038/s41416-019-0551-1
pmc: PMC6888814
doi:
Substances chimiques
Antineoplastic Agents
0
RNA, Messenger
0
Transcription Factor RelA
0
Bortezomib
69G8BD63PP
O(6)-Methylguanine-DNA Methyltransferase
EC 2.1.1.63
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
545-555Références
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).
doi: 10.1056/NEJMoa043330
Srivenugopal, K. S., Yuan, X. H., Friedman, H. S. & Ali-Osman, F. Ubiquitination-dependent proteolysis of O6-methylguanine-DNA methyltransferase in human and murine tumour cells following inactivation with O6-benzylguanine or 1,3-bis(2-chloroethyl)-1-nitrosourea. Biochemistry 35, 1328–1334 (1996).
doi: 10.1021/bi9518205
Esteller, M., Garcia-Foncillas, J., Andion, E., Goodman, S. N., Hidalgo, O. F., Vanaclocha, V. et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354 (2000).
doi: 10.1056/NEJM200011093431901
Hegi, M. E., Diserens, A. C., Gorlia, T., Hamou, M. F., de Tribolet, N., Weller, M. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
doi: 10.1056/NEJMoa043331
Rasheed, B. K., McLendon, R. E., Friedman, H. S., Friedman, A. H., Fuchs, H. E., Bigner, D. D. et al. Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. Oncogene 10, 2243–2246 (1995).
pubmed: 7784070
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
doi: 10.1126/science.1164382
Lavon, I., Fuchs, D., Zrihan, D., Efroni, G., Zelikovitch, B., Fellig, Y. et al. Novel mechanism whereby nuclear factor kappaB mediates DNA damage repair through regulation of O(6)-methylguanine-DNA-methyltransferase. Cancer Res. 67, 8952–8959 (2007).
doi: 10.1158/0008-5472.CAN-06-3820
Barnes, P. J. & Karin, M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).
doi: 10.1056/NEJM199704103361506
Palombella, V. J., Rando, O. J., Goldberg, A. L. & Maniatis, T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78, 773–785 (1994).
doi: 10.1016/S0092-8674(94)90482-0
Paramore, A. & Frantz, S. Bortezomib. Nat. Rev. Drug Disco. 2, 611–612 (2003).
doi: 10.1038/nrd1159
Stapnes, C., Doskeland, A. P., Hatfield, K., Ersvaer, E., Ryningen, A., Lorens, J. B. et al. The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells. Br. J. Haematol. 136, 814–828 (2007).
doi: 10.1111/j.1365-2141.2007.06504.x
Vlachostergios, P. J., Hatzidaki, E., Befani, C. D., Liakos, P. & Papandreou, C. N. Bortezomib overcomes MGMT-related resistance of glioblastoma cell lines to temozolomide in a schedule-dependent manner. Invest. New Drugs 31, 1169–1181 (2013).
doi: 10.1007/s10637-013-9968-1
Vlachostergios, P. J., Hatzidaki, E., Stathakis, N. E., Koukoulis, G. K. & Papandreou, C. N. Bortezomib downregulates MGMT expression in T98G glioblastoma cells. Cell Mol. Neurobiol. 33, 313–318 (2013).
doi: 10.1007/s10571-013-9910-2
Zeng, R. X., Zhang, Y. B., Fan, Y. & Wu, G. L. p62/SQSTM1 is involved in caspase-8 associated cell death induced by proteasome inhibitor MG132 in U87MG cells. Cell Biol. Int. 38, 1221–1226 (2014).
doi: 10.1002/cbin.10311
Bota, D. A., Alexandru, D., Keir, S. T., Bigner, D., Vredenburgh, J. & Friedman, H. S. Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis. J. Neurosurg. 119, 1415–1423 (2013).
doi: 10.3171/2013.7.JNS1323
Labussiere, M., Pinel, S., Delfortrie, S., Plenat, F. & Chastagner, P. Proteasome inhibition by bortezomib does not translate into efficacy on two malignant glioma xenografts. Oncol. Rep. 20, 1283–1287 (2008).
pubmed: 18949434
McCracken, D. J., Celano, E. C., Voloschin, A. D., Read, W. L. & Olson, J. J. Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma. J. Neurooncol. 130, 193–201 (2016).
doi: 10.1007/s11060-016-2234-6
Kubicek, G. J., Werner-Wasik, M., Machtay, M., Mallon, G., Myers, T., Ramirez, M. et al. Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies. Int J. Radiat. Oncol. Biol. Phys. 74, 433–439 (2009).
doi: 10.1016/j.ijrobp.2008.08.050
Odia, Y., Kreisl, T. N., Aregawi, D., Innis, E. K. & Fine, H. A. A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas. J. Neurooncol. 125, 191–195 (2015).
doi: 10.1007/s11060-015-1894-y
Friday, B. B., Anderson, S. K., Buckner, J., Yu, C., Giannini, C., Geoffroy, F. et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro. Oncol. 14, 215–221 (2012).
doi: 10.1093/neuonc/nor198
Phuphanich, S., Supko, J. G., Carson, K. A., Grossman, S. A., Burt Nabors, L., Mikkelsen, T. et al. Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma. J. Neurooncol. 100, 95–103 (2010).
doi: 10.1007/s11060-010-0143-7
Portnow, J., Frankel, P., Koehler, S., Twardowski, P., Shibata, S., Martel, C. et al. A phase I study of bortezomib and temozolomide in patients with advanced solid tumours. Cancer Chemother. Pharm. 69, 505–514 (2012).
doi: 10.1007/s00280-011-1721-x
Kong, X. T., Nguyen, N. T., Choi, Y. J., Zhang, G., Nguyen, H. N., Filka, E. et al. Phase 2 study of bortezomib combined with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme: safety and efficacy assessment. Int J. Radiat. Oncol. Biol. Phys. 100, 1195–1203 (2018).
doi: 10.1016/j.ijrobp.2018.01.001
Dolan, M. E., Mitchell, R. B., Mummert, C., Moschel, R. C. & Pegg, A. E. Effect of O6-benzylguanine analogues on sensitivity of human tumour cells to the cytotoxic effects of alkylating agents. Cancer Res 51, 3367–3372 (1991).
pubmed: 1647266
Sakariassen, P. O., Prestegarden, L., Wang, J., Skaftnesmo, K. O., Mahesparan, R., Molthoff, C. et al. Angiogenesis-independent tumour growth mediated by stem-like cancer cells. Proc. Natl Acad. Sci. USA 103, 16466–16471 (2006).
doi: 10.1073/pnas.0607668103
Wang, J., Miletic, H., Sakariassen, P. O., Huszthy, P. C., Jacobsen, H., Brekka, N. et al. A reproducible brain tumour model established from human glioblastoma biopsies. BMC Cancer 9, 465 (2009).
doi: 10.1186/1471-2407-9-465
Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 8, e1000412 (2010).
doi: 10.1371/journal.pbio.1000412
U.S. Department of health and human services food and drug administration CfdearC. Guidance for industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Pharmacol. Toxicol. (2005). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers
Svendsen, A., Verhoeff, J. J., Immervoll, H., Brogger, J. C., Kmiecik, J., Poli, A. et al. Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta Neuropathol. 122, 495–510 (2011).
doi: 10.1007/s00401-011-0867-2
Chekenya, M., Enger, P. O., Thorsen, F., Tysnes, B. B., Al-Sarraj, S., Read, T. A. et al. The glial precursor proteoglycan, NG2, is expressed on tumour neovasculature by vascular pericytes in human malignant brain tumours. Neuropathol. Appl. Neurobiol. 28, 367–380 (2002).
doi: 10.1046/j.1365-2990.2002.00412.x
Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50, 163–170 (1966).
pubmed: 5910392
Lonial, S., Waller, E. K., Richardson, P. G., Jagannath, S., Orlowski, R. Z., Giver, C. R. et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106, 3777–3784 (2005).
doi: 10.1182/blood-2005-03-1173
Brassesco, M. S., Roberto, G. M., Morales, A. G., Oliveira, J. C., Delsin, L. E., Pezuk, J. A. et al. Inhibition of NF-kappa B by dehydroxymethylepoxyquinomicin suppresses invasion and synergistically potentiates temozolomide and gamma -radiation cytotoxicity in glioblastoma cells. Chemother. Res. Pr. 2013, 593020 (2013).
Han, S. J., Rolston, J. D., Molinaro, A. M., Clarke, J. L., Prados, M. D., Chang, S. M. et al. Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma. Neuro Oncol. 16, 1255–1262 (2014).
doi: 10.1093/neuonc/nou044
Xu-Welliver, M. & Pegg, A. E. Degradation of the alkylated form of the DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase. Carcinogenesis 23, 823–830 (2002).
doi: 10.1093/carcin/23.5.823
Viel, T., Monfared, P., Schelhaas, S., Fricke, I. B., Kuhlmann, M. T., Fraefel, C. et al. Optimizing glioblastoma temozolomide chemotherapy employing lentiviral-based anti-MGMT shRNA technology. Mol. Ther. 21, 570–579 (2013).
doi: 10.1038/mt.2012.278
Quinn, J. A., Pluda, J., Dolan, M. E., Delaney, S., Kaplan, R., Rich, J. N. et al. Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma. J. Clin. Oncol. 20, 2277–2283 (2002).
doi: 10.1200/JCO.2002.09.084
Quinn, J. A., Desjardins, A., Weingart, J., Brem, H., Dolan, M. E., Delaney, S. M. et al. Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J. Clin. Oncol. 23, 7178–7187 (2005).
doi: 10.1200/JCO.2005.06.502
Weingart, J., Grossman, S. A., Carson, K. A., Fisher, J. D., Delaney, S. M., Rosenblum, M. L. et al. Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumour therapy CNS consortium trial. J. Clin. Oncol. 25, 399–404 (2007).
doi: 10.1200/JCO.2006.06.6290
Harris, L. C., Remack, J. S., Houghton, P. J. & Brent, T. P. Wild-type p53 suppresses transcription of the human O6-methylguanine-DNA methyltransferase gene. Cancer Res. 56, 2029–2032 (1996).
pubmed: 8616846
Smalley, S., Chalmers, A. J. & Morley, S. J. mTOR inhibition and levels of the DNA repair protein MGMT in T98G glioblastoma cells. Mol. Cancer 13, 144 (2014).
doi: 10.1186/1476-4598-13-144
Schwartz, R. & Davidson, T. Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncol. (Williston Park) 18(14 Suppl 11), 14–21 (2004).
Englehard, H. H. & Groothius, D. G. The Blood-Brain Barrier: Structure, Function and Response to Neoplasia. In Berger M, Wilson C. (eds) The Gliomas. p. 115–121. (Philadelphia: WB Saunders, 1998).
Olson J. J. B. J. & Zhang, Z. Proteasome Inhibitor Therapy in a Brain Tumour Model. (Humana Press, Totowa, NJ, 2004).
Raizer, J. J., Chandler, J. P., Ferrarese, R., Grimm, S. A., Levy, R. M., Muro, K. et al. A phase II trial evaluating the effects and intra-tumoural penetration of bortezomib in patients with recurrent malignant gliomas. J. Neurooncol. 129, 139–146 (2016).
doi: 10.1007/s11060-016-2156-3
Liu, Y., Liu, P., Wen, W., James, M. A., Wang, Y., Bailey-Wilson, J. E. et al. Haplotype and cell proliferation analyses of candidate lung cancer susceptibility genes on chromosome 15q24-25.1. Cancer Res. 69, 7844–7850 (2009).
doi: 10.1158/0008-5472.CAN-09-1833
Vizcaino, J. A., Deutsch, E. W., Wang, R., Csordas, A., Reisinger, F., Rios, D. et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat. Biotechnol. 32, 223–226 (2014).
doi: 10.1038/nbt.2839