Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide

The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combi...
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Autor*in:	Ozgiray, Erkin [verfasserIn] Sogutlu, Fatma Biray Avci, Cigir

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	IDH-mutant glioma Temozolomide DNA damage response AZD7762 Polploidy

Anmerkung:	© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Übergeordnetes Werk:	Enthalten in: Medical oncology - New York, NY : Springer, 1984, 39(2022), 11 vom: 16. Aug.
Übergeordnetes Werk:	volume:39 ; year:2022 ; number:11 ; day:16 ; month:08

Links:	Volltext

DOI / URN:	10.1007/s12032-022-01769-x

Katalog-ID:	SPR047864044

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author_variant	e o eo f s fs a c b ac acb
matchkey_str	article:1559131X:2022----::h1ihbtrz76ehneteucpiiiyfdmtnban
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allfields	10.1007/s12032-022-01769-x doi (DE-627)SPR047864044 (SPR)s12032-022-01769-x-e DE-627 ger DE-627 rakwb eng Ozgiray, Erkin verfasserin (orcid)0000-0002-1156-9468 aut Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. IDH-mutant glioma (dpeaa)DE-He213 Temozolomide (dpeaa)DE-He213 DNA damage response (dpeaa)DE-He213 AZD7762 (dpeaa)DE-He213 Polploidy (dpeaa)DE-He213 Sogutlu, Fatma aut Biray Avci, Cigir (orcid)0000-0001-8251-4520 aut Enthalten in Medical oncology New York, NY : Springer, 1984 39(2022), 11 vom: 16. Aug. (DE-627)320468240 (DE-600)2008172-8 1559-131X nnns volume:39 year:2022 number:11 day:16 month:08 https://dx.doi.org/10.1007/s12032-022-01769-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 39 2022 11 16 08
spelling	10.1007/s12032-022-01769-x doi (DE-627)SPR047864044 (SPR)s12032-022-01769-x-e DE-627 ger DE-627 rakwb eng Ozgiray, Erkin verfasserin (orcid)0000-0002-1156-9468 aut Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. IDH-mutant glioma (dpeaa)DE-He213 Temozolomide (dpeaa)DE-He213 DNA damage response (dpeaa)DE-He213 AZD7762 (dpeaa)DE-He213 Polploidy (dpeaa)DE-He213 Sogutlu, Fatma aut Biray Avci, Cigir (orcid)0000-0001-8251-4520 aut Enthalten in Medical oncology New York, NY : Springer, 1984 39(2022), 11 vom: 16. Aug. (DE-627)320468240 (DE-600)2008172-8 1559-131X nnns volume:39 year:2022 number:11 day:16 month:08 https://dx.doi.org/10.1007/s12032-022-01769-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 39 2022 11 16 08
allfields_unstemmed	10.1007/s12032-022-01769-x doi (DE-627)SPR047864044 (SPR)s12032-022-01769-x-e DE-627 ger DE-627 rakwb eng Ozgiray, Erkin verfasserin (orcid)0000-0002-1156-9468 aut Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. IDH-mutant glioma (dpeaa)DE-He213 Temozolomide (dpeaa)DE-He213 DNA damage response (dpeaa)DE-He213 AZD7762 (dpeaa)DE-He213 Polploidy (dpeaa)DE-He213 Sogutlu, Fatma aut Biray Avci, Cigir (orcid)0000-0001-8251-4520 aut Enthalten in Medical oncology New York, NY : Springer, 1984 39(2022), 11 vom: 16. Aug. (DE-627)320468240 (DE-600)2008172-8 1559-131X nnns volume:39 year:2022 number:11 day:16 month:08 https://dx.doi.org/10.1007/s12032-022-01769-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 39 2022 11 16 08
allfieldsGer	10.1007/s12032-022-01769-x doi (DE-627)SPR047864044 (SPR)s12032-022-01769-x-e DE-627 ger DE-627 rakwb eng Ozgiray, Erkin verfasserin (orcid)0000-0002-1156-9468 aut Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. IDH-mutant glioma (dpeaa)DE-He213 Temozolomide (dpeaa)DE-He213 DNA damage response (dpeaa)DE-He213 AZD7762 (dpeaa)DE-He213 Polploidy (dpeaa)DE-He213 Sogutlu, Fatma aut Biray Avci, Cigir (orcid)0000-0001-8251-4520 aut Enthalten in Medical oncology New York, NY : Springer, 1984 39(2022), 11 vom: 16. Aug. (DE-627)320468240 (DE-600)2008172-8 1559-131X nnns volume:39 year:2022 number:11 day:16 month:08 https://dx.doi.org/10.1007/s12032-022-01769-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 39 2022 11 16 08
allfieldsSound	10.1007/s12032-022-01769-x doi (DE-627)SPR047864044 (SPR)s12032-022-01769-x-e DE-627 ger DE-627 rakwb eng Ozgiray, Erkin verfasserin (orcid)0000-0002-1156-9468 aut Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. IDH-mutant glioma (dpeaa)DE-He213 Temozolomide (dpeaa)DE-He213 DNA damage response (dpeaa)DE-He213 AZD7762 (dpeaa)DE-He213 Polploidy (dpeaa)DE-He213 Sogutlu, Fatma aut Biray Avci, Cigir (orcid)0000-0001-8251-4520 aut Enthalten in Medical oncology New York, NY : Springer, 1984 39(2022), 11 vom: 16. Aug. (DE-627)320468240 (DE-600)2008172-8 1559-131X nnns volume:39 year:2022 number:11 day:16 month:08 https://dx.doi.org/10.1007/s12032-022-01769-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 39 2022 11 16 08
language	English
source	Enthalten in Medical oncology 39(2022), 11 vom: 16. Aug. volume:39 year:2022 number:11 day:16 month:08
sourceStr	Enthalten in Medical oncology 39(2022), 11 vom: 16. Aug. volume:39 year:2022 number:11 day:16 month:08
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	IDH-mutant glioma Temozolomide DNA damage response AZD7762 Polploidy
isfreeaccess_bool	false
container_title	Medical oncology
authorswithroles_txt_mv	Ozgiray, Erkin @@aut@@ Sogutlu, Fatma @@aut@@ Biray Avci, Cigir @@aut@@
publishDateDaySort_date	2022-08-16T00:00:00Z
hierarchy_top_id	320468240
id	SPR047864044
language_de	englisch
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author	Ozgiray, Erkin
spellingShingle	Ozgiray, Erkin misc IDH-mutant glioma misc Temozolomide misc DNA damage response misc AZD7762 misc Polploidy Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide
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topic_title	Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide IDH-mutant glioma (dpeaa)DE-He213 Temozolomide (dpeaa)DE-He213 DNA damage response (dpeaa)DE-He213 AZD7762 (dpeaa)DE-He213 Polploidy (dpeaa)DE-He213
topic	misc IDH-mutant glioma misc Temozolomide misc DNA damage response misc AZD7762 misc Polploidy
topic_unstemmed	misc IDH-mutant glioma misc Temozolomide misc DNA damage response misc AZD7762 misc Polploidy
topic_browse	misc IDH-mutant glioma misc Temozolomide misc DNA damage response misc AZD7762 misc Polploidy
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title	Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide
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title_full	Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide
author_sort	Ozgiray, Erkin
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author_browse	Ozgiray, Erkin Sogutlu, Fatma Biray Avci, Cigir
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title_sort	chk1/2 inhibitor azd7762 enhances the susceptibility of idh-mutant brain cancer cells to temozolomide
title_auth	Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide
abstract	The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
abstractGer	The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
abstract_unstemmed	The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose–effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in $ G_{2} $/M arrest from 24 to 48 h, and cells in the $ G_{2} $/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. Graphical abstract In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
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container_issue	11
title_short	Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide
url	https://dx.doi.org/10.1007/s12032-022-01769-x
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author2	Sogutlu, Fatma Biray Avci, Cigir
author2Str	Sogutlu, Fatma Biray Avci, Cigir
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doi_str	10.1007/s12032-022-01769-x
up_date	2024-07-03T15:29:44.909Z
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