Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer
Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Kang, Sun Kyoung [verfasserIn] Bae, Hyun Joo [verfasserIn] Kwon, Woo Sun [verfasserIn] Kim, Tae Soo [verfasserIn] Kim, Kyoo Hyun [verfasserIn] Park, Sejung [verfasserIn] Yu, Seo Young [verfasserIn] Hwang, Jihyun [verfasserIn] Park, Juin [verfasserIn] Chung, Hyun Cheol [verfasserIn] Rha, Sun Young [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Anmerkung: |
© Springer Nature Switzerland AG 2021 |
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| Übergeordnetes Werk: |
Enthalten in: Cellular oncology - Amsterdam [u.a.] : IOS Press, 2004, 44(2021), 6 vom: 18. Nov., Seite 1387-1403 |
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| Übergeordnetes Werk: |
volume:44 ; year:2021 ; number:6 ; day:18 ; month:11 ; pages:1387-1403 |
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| DOI / URN: |
10.1007/s13402-021-00647-4 |
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| Katalog-ID: |
SPR045751471 |
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| 520 | |a Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. | ||
| 650 | 4 | |a Gastric cancer |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Epigenetic regulation |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a BET inhibitor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Paclitaxel |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Kim, Kyoo Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Sejung |e verfasserin |4 aut | |
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| 700 | 1 | |a Hwang, Jihyun |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Juin |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Hyun Cheol |e verfasserin |4 aut | |
| 700 | 1 | |a Rha, Sun Young |e verfasserin |4 aut | |
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10.1007/s13402-021-00647-4 doi (DE-627)SPR045751471 (SPR)s13402-021-00647-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE Kang, Sun Kyoung verfasserin aut Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Nature Switzerland AG 2021 Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. Gastric cancer (dpeaa)DE-He213 Epigenetic regulation (dpeaa)DE-He213 BET protein (dpeaa)DE-He213 BET inhibitor (dpeaa)DE-He213 Paclitaxel (dpeaa)DE-He213 Combination therapy (dpeaa)DE-He213 GC organoid (dpeaa)DE-He213 Bae, Hyun Joo verfasserin aut Kwon, Woo Sun verfasserin aut Kim, Tae Soo verfasserin aut Kim, Kyoo Hyun verfasserin aut Park, Sejung verfasserin aut Yu, Seo Young verfasserin aut Hwang, Jihyun verfasserin aut Park, Juin verfasserin aut Chung, Hyun Cheol verfasserin aut Rha, Sun Young verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 44(2021), 6 vom: 18. Nov., Seite 1387-1403 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:44 year:2021 number:6 day:18 month:11 pages:1387-1403 https://dx.doi.org/10.1007/s13402-021-00647-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 44 2021 6 18 11 1387-1403 |
| spelling |
10.1007/s13402-021-00647-4 doi (DE-627)SPR045751471 (SPR)s13402-021-00647-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE Kang, Sun Kyoung verfasserin aut Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Nature Switzerland AG 2021 Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. Gastric cancer (dpeaa)DE-He213 Epigenetic regulation (dpeaa)DE-He213 BET protein (dpeaa)DE-He213 BET inhibitor (dpeaa)DE-He213 Paclitaxel (dpeaa)DE-He213 Combination therapy (dpeaa)DE-He213 GC organoid (dpeaa)DE-He213 Bae, Hyun Joo verfasserin aut Kwon, Woo Sun verfasserin aut Kim, Tae Soo verfasserin aut Kim, Kyoo Hyun verfasserin aut Park, Sejung verfasserin aut Yu, Seo Young verfasserin aut Hwang, Jihyun verfasserin aut Park, Juin verfasserin aut Chung, Hyun Cheol verfasserin aut Rha, Sun Young verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 44(2021), 6 vom: 18. Nov., Seite 1387-1403 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:44 year:2021 number:6 day:18 month:11 pages:1387-1403 https://dx.doi.org/10.1007/s13402-021-00647-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 44 2021 6 18 11 1387-1403 |
| allfields_unstemmed |
10.1007/s13402-021-00647-4 doi (DE-627)SPR045751471 (SPR)s13402-021-00647-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE Kang, Sun Kyoung verfasserin aut Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Nature Switzerland AG 2021 Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. Gastric cancer (dpeaa)DE-He213 Epigenetic regulation (dpeaa)DE-He213 BET protein (dpeaa)DE-He213 BET inhibitor (dpeaa)DE-He213 Paclitaxel (dpeaa)DE-He213 Combination therapy (dpeaa)DE-He213 GC organoid (dpeaa)DE-He213 Bae, Hyun Joo verfasserin aut Kwon, Woo Sun verfasserin aut Kim, Tae Soo verfasserin aut Kim, Kyoo Hyun verfasserin aut Park, Sejung verfasserin aut Yu, Seo Young verfasserin aut Hwang, Jihyun verfasserin aut Park, Juin verfasserin aut Chung, Hyun Cheol verfasserin aut Rha, Sun Young verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 44(2021), 6 vom: 18. Nov., Seite 1387-1403 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:44 year:2021 number:6 day:18 month:11 pages:1387-1403 https://dx.doi.org/10.1007/s13402-021-00647-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 44 2021 6 18 11 1387-1403 |
| allfieldsGer |
10.1007/s13402-021-00647-4 doi (DE-627)SPR045751471 (SPR)s13402-021-00647-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE Kang, Sun Kyoung verfasserin aut Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Nature Switzerland AG 2021 Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. Gastric cancer (dpeaa)DE-He213 Epigenetic regulation (dpeaa)DE-He213 BET protein (dpeaa)DE-He213 BET inhibitor (dpeaa)DE-He213 Paclitaxel (dpeaa)DE-He213 Combination therapy (dpeaa)DE-He213 GC organoid (dpeaa)DE-He213 Bae, Hyun Joo verfasserin aut Kwon, Woo Sun verfasserin aut Kim, Tae Soo verfasserin aut Kim, Kyoo Hyun verfasserin aut Park, Sejung verfasserin aut Yu, Seo Young verfasserin aut Hwang, Jihyun verfasserin aut Park, Juin verfasserin aut Chung, Hyun Cheol verfasserin aut Rha, Sun Young verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 44(2021), 6 vom: 18. Nov., Seite 1387-1403 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:44 year:2021 number:6 day:18 month:11 pages:1387-1403 https://dx.doi.org/10.1007/s13402-021-00647-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 44 2021 6 18 11 1387-1403 |
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10.1007/s13402-021-00647-4 doi (DE-627)SPR045751471 (SPR)s13402-021-00647-4-e DE-627 ger DE-627 rakwb eng 610 570 ASE Kang, Sun Kyoung verfasserin aut Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer Nature Switzerland AG 2021 Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. Gastric cancer (dpeaa)DE-He213 Epigenetic regulation (dpeaa)DE-He213 BET protein (dpeaa)DE-He213 BET inhibitor (dpeaa)DE-He213 Paclitaxel (dpeaa)DE-He213 Combination therapy (dpeaa)DE-He213 GC organoid (dpeaa)DE-He213 Bae, Hyun Joo verfasserin aut Kwon, Woo Sun verfasserin aut Kim, Tae Soo verfasserin aut Kim, Kyoo Hyun verfasserin aut Park, Sejung verfasserin aut Yu, Seo Young verfasserin aut Hwang, Jihyun verfasserin aut Park, Juin verfasserin aut Chung, Hyun Cheol verfasserin aut Rha, Sun Young verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 44(2021), 6 vom: 18. Nov., Seite 1387-1403 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:44 year:2021 number:6 day:18 month:11 pages:1387-1403 https://dx.doi.org/10.1007/s13402-021-00647-4 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 44 2021 6 18 11 1387-1403 |
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English |
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Enthalten in Cellular oncology 44(2021), 6 vom: 18. Nov., Seite 1387-1403 volume:44 year:2021 number:6 day:18 month:11 pages:1387-1403 |
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Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer |
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Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. © Springer Nature Switzerland AG 2021 |
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Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. © Springer Nature Switzerland AG 2021 |
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Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity. © Springer Nature Switzerland AG 2021 |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR045751471</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519223212.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">211207s2021 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s13402-021-00647-4</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR045751471</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s13402-021-00647-4-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">610</subfield><subfield code="a">570</subfield><subfield code="q">ASE</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Kang, Sun Kyoung</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Springer Nature Switzerland AG 2021</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Purpose Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy. Methods The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model. Results We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect. Conclusions Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Gastric cancer</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Epigenetic regulation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BET protein</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">BET inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Paclitaxel</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Combination therapy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">GC organoid</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bae, Hyun Joo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kwon, Woo Sun</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kim, Tae Soo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kim, Kyoo Hyun</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Park, Sejung</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yu, Seo Young</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Hwang, Jihyun</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Park, Juin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Chung, Hyun Cheol</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rha, Sun Young</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Cellular oncology</subfield><subfield code="d">Amsterdam [u.a.] : IOS Press, 2004</subfield><subfield code="g">44(2021), 6 vom: 18. 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