Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas
Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our prev...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Maletzki, Claudia [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017transfer abstract |
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| Schlagwörter: |
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| Umfang: |
10 |
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| Übergeordnetes Werk: |
Enthalten in: Ambiguous information and dilation: An experiment - Shishkin, Denis ELSEVIER, 2023, a journal of molecular and biochemical toxicology, Amsterdam [u.a.] |
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| Übergeordnetes Werk: |
volume:278 ; year:2017 ; day:25 ; month:12 ; pages:179-188 ; extent:10 |
| Links: |
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| DOI / URN: |
10.1016/j.cbi.2017.10.007 |
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ELV04114855X |
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| 520 | |a Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. | ||
| 520 | |a Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. | ||
| 650 | 7 | |a Cellular metabolism |2 Elsevier | |
| 650 | 7 | |a Arginine-catabolizing enzymes |2 Elsevier | |
| 650 | 7 | |a Radiation |2 Elsevier | |
| 650 | 7 | |a Combination therapy |2 Elsevier | |
| 650 | 7 | |a Patient-derived GBM cell lines |2 Elsevier | |
| 700 | 1 | |a Rosche, Yvonne |4 oth | |
| 700 | 1 | |a Riess, Christin |4 oth | |
| 700 | 1 | |a Scholz, Aline |4 oth | |
| 700 | 1 | |a William, Doreen |4 oth | |
| 700 | 1 | |a Classen, Carl Friedrich |4 oth | |
| 700 | 1 | |a Kreikemeyer, Bernd |4 oth | |
| 700 | 1 | |a Linnebacher, Michael |4 oth | |
| 700 | 1 | |a Fiedler, Tomas |4 oth | |
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10.1016/j.cbi.2017.10.007 doi GBV00000000000095A.pica (DE-627)ELV04114855X (ELSEVIER)S0009-2797(17)30787-1 DE-627 ger DE-627 rakwb eng 570 540 570 DE-600 540 DE-600 330 VZ 31.00 bkl 83.10 bkl Maletzki, Claudia verfasserin aut Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas 2017transfer abstract 10 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Cellular metabolism Elsevier Arginine-catabolizing enzymes Elsevier Radiation Elsevier Combination therapy Elsevier Patient-derived GBM cell lines Elsevier Rosche, Yvonne oth Riess, Christin oth Scholz, Aline oth William, Doreen oth Classen, Carl Friedrich oth Kreikemeyer, Bernd oth Linnebacher, Michael oth Fiedler, Tomas oth Enthalten in Elsevier Science Shishkin, Denis ELSEVIER Ambiguous information and dilation: An experiment 2023 a journal of molecular and biochemical toxicology Amsterdam [u.a.] (DE-627)ELV009268340 volume:278 year:2017 day:25 month:12 pages:179-188 extent:10 https://doi.org/10.1016/j.cbi.2017.10.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OPC-MAT 31.00 Mathematik: Allgemeines VZ 83.10 Wirtschaftstheorie: Allgemeines VZ AR 278 2017 25 1225 179-188 10 045F 570 |
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10.1016/j.cbi.2017.10.007 doi GBV00000000000095A.pica (DE-627)ELV04114855X (ELSEVIER)S0009-2797(17)30787-1 DE-627 ger DE-627 rakwb eng 570 540 570 DE-600 540 DE-600 330 VZ 31.00 bkl 83.10 bkl Maletzki, Claudia verfasserin aut Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas 2017transfer abstract 10 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Cellular metabolism Elsevier Arginine-catabolizing enzymes Elsevier Radiation Elsevier Combination therapy Elsevier Patient-derived GBM cell lines Elsevier Rosche, Yvonne oth Riess, Christin oth Scholz, Aline oth William, Doreen oth Classen, Carl Friedrich oth Kreikemeyer, Bernd oth Linnebacher, Michael oth Fiedler, Tomas oth Enthalten in Elsevier Science Shishkin, Denis ELSEVIER Ambiguous information and dilation: An experiment 2023 a journal of molecular and biochemical toxicology Amsterdam [u.a.] (DE-627)ELV009268340 volume:278 year:2017 day:25 month:12 pages:179-188 extent:10 https://doi.org/10.1016/j.cbi.2017.10.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OPC-MAT 31.00 Mathematik: Allgemeines VZ 83.10 Wirtschaftstheorie: Allgemeines VZ AR 278 2017 25 1225 179-188 10 045F 570 |
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10.1016/j.cbi.2017.10.007 doi GBV00000000000095A.pica (DE-627)ELV04114855X (ELSEVIER)S0009-2797(17)30787-1 DE-627 ger DE-627 rakwb eng 570 540 570 DE-600 540 DE-600 330 VZ 31.00 bkl 83.10 bkl Maletzki, Claudia verfasserin aut Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas 2017transfer abstract 10 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Cellular metabolism Elsevier Arginine-catabolizing enzymes Elsevier Radiation Elsevier Combination therapy Elsevier Patient-derived GBM cell lines Elsevier Rosche, Yvonne oth Riess, Christin oth Scholz, Aline oth William, Doreen oth Classen, Carl Friedrich oth Kreikemeyer, Bernd oth Linnebacher, Michael oth Fiedler, Tomas oth Enthalten in Elsevier Science Shishkin, Denis ELSEVIER Ambiguous information and dilation: An experiment 2023 a journal of molecular and biochemical toxicology Amsterdam [u.a.] (DE-627)ELV009268340 volume:278 year:2017 day:25 month:12 pages:179-188 extent:10 https://doi.org/10.1016/j.cbi.2017.10.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OPC-MAT 31.00 Mathematik: Allgemeines VZ 83.10 Wirtschaftstheorie: Allgemeines VZ AR 278 2017 25 1225 179-188 10 045F 570 |
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10.1016/j.cbi.2017.10.007 doi GBV00000000000095A.pica (DE-627)ELV04114855X (ELSEVIER)S0009-2797(17)30787-1 DE-627 ger DE-627 rakwb eng 570 540 570 DE-600 540 DE-600 330 VZ 31.00 bkl 83.10 bkl Maletzki, Claudia verfasserin aut Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas 2017transfer abstract 10 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Cellular metabolism Elsevier Arginine-catabolizing enzymes Elsevier Radiation Elsevier Combination therapy Elsevier Patient-derived GBM cell lines Elsevier Rosche, Yvonne oth Riess, Christin oth Scholz, Aline oth William, Doreen oth Classen, Carl Friedrich oth Kreikemeyer, Bernd oth Linnebacher, Michael oth Fiedler, Tomas oth Enthalten in Elsevier Science Shishkin, Denis ELSEVIER Ambiguous information and dilation: An experiment 2023 a journal of molecular and biochemical toxicology Amsterdam [u.a.] (DE-627)ELV009268340 volume:278 year:2017 day:25 month:12 pages:179-188 extent:10 https://doi.org/10.1016/j.cbi.2017.10.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OPC-MAT 31.00 Mathematik: Allgemeines VZ 83.10 Wirtschaftstheorie: Allgemeines VZ AR 278 2017 25 1225 179-188 10 045F 570 |
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10.1016/j.cbi.2017.10.007 doi GBV00000000000095A.pica (DE-627)ELV04114855X (ELSEVIER)S0009-2797(17)30787-1 DE-627 ger DE-627 rakwb eng 570 540 570 DE-600 540 DE-600 330 VZ 31.00 bkl 83.10 bkl Maletzki, Claudia verfasserin aut Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas 2017transfer abstract 10 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Cellular metabolism Elsevier Arginine-catabolizing enzymes Elsevier Radiation Elsevier Combination therapy Elsevier Patient-derived GBM cell lines Elsevier Rosche, Yvonne oth Riess, Christin oth Scholz, Aline oth William, Doreen oth Classen, Carl Friedrich oth Kreikemeyer, Bernd oth Linnebacher, Michael oth Fiedler, Tomas oth Enthalten in Elsevier Science Shishkin, Denis ELSEVIER Ambiguous information and dilation: An experiment 2023 a journal of molecular and biochemical toxicology Amsterdam [u.a.] (DE-627)ELV009268340 volume:278 year:2017 day:25 month:12 pages:179-188 extent:10 https://doi.org/10.1016/j.cbi.2017.10.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OPC-MAT 31.00 Mathematik: Allgemeines VZ 83.10 Wirtschaftstheorie: Allgemeines VZ AR 278 2017 25 1225 179-188 10 045F 570 |
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Deciphering molecular mechanisms of arginine deiminase-based therapy – Comparative response analysis in paired human primary and recurrent glioblastomas |
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Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. |
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Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. |
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Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. |
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Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations.</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Cellular metabolism</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Arginine-catabolizing enzymes</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Radiation</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Combination therapy</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Patient-derived GBM cell lines</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rosche, Yvonne</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Riess, Christin</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Scholz, Aline</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">William, Doreen</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Classen, Carl Friedrich</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kreikemeyer, Bernd</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Linnebacher, Michael</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fiedler, Tomas</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Elsevier Science</subfield><subfield code="a">Shishkin, Denis ELSEVIER</subfield><subfield code="t">Ambiguous information and dilation: An experiment</subfield><subfield code="d">2023</subfield><subfield code="d">a journal of molecular and biochemical toxicology</subfield><subfield code="g">Amsterdam [u.a.]</subfield><subfield code="w">(DE-627)ELV009268340</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:278</subfield><subfield code="g">year:2017</subfield><subfield code="g">day:25</subfield><subfield code="g">month:12</subfield><subfield code="g">pages:179-188</subfield><subfield code="g">extent:10</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.cbi.2017.10.007</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-MAT</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">31.00</subfield><subfield code="j">Mathematik: Allgemeines</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">83.10</subfield><subfield code="j">Wirtschaftstheorie: Allgemeines</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">278</subfield><subfield code="j">2017</subfield><subfield code="b">25</subfield><subfield code="c">1225</subfield><subfield code="h">179-188</subfield><subfield code="g">10</subfield></datafield><datafield tag="953" ind1=" " ind2=" "><subfield code="2">045F</subfield><subfield code="a">570</subfield></datafield></record></collection>
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