Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status
Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present wo...
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| Autor*in: |
Min-Wu Chao [verfasserIn] Li-Hsun Chang [verfasserIn] Huang-Ju Tu [verfasserIn] Chao-Di Chang [verfasserIn] Mei-Jung Lai [verfasserIn] Yi-Ying Chen [verfasserIn] Jing-Ping Liou [verfasserIn] Che-Ming Teng [verfasserIn] Shiow-Lin Pan [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2019 |
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In: Clinical Epigenetics ; 11(2019), 1, Seite 14 volume:11 ; year:2019 ; number:1 ; pages:14 |
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| DOI / URN: |
10.1186/s13148-019-0681-6 |
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| Katalog-ID: |
DOAJ046777075 |
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| 520 | |a Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. | ||
| 650 | 4 | |a Pancreatic cancer | |
| 650 | 4 | |a MPT0E028 | |
| 650 | 4 | |a MEK inhibitor | |
| 650 | 4 | |a EGFR | |
| 650 | 4 | |a K-Ras status | |
| 653 | 0 | |a Medicine | |
| 653 | 0 | |a R | |
| 653 | 0 | |a Genetics | |
| 700 | 0 | |a Li-Hsun Chang |e verfasserin |4 aut | |
| 700 | 0 | |a Huang-Ju Tu |e verfasserin |4 aut | |
| 700 | 0 | |a Chao-Di Chang |e verfasserin |4 aut | |
| 700 | 0 | |a Mei-Jung Lai |e verfasserin |4 aut | |
| 700 | 0 | |a Yi-Ying Chen |e verfasserin |4 aut | |
| 700 | 0 | |a Jing-Ping Liou |e verfasserin |4 aut | |
| 700 | 0 | |a Che-Ming Teng |e verfasserin |4 aut | |
| 700 | 0 | |a Shiow-Lin Pan |e verfasserin |4 aut | |
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10.1186/s13148-019-0681-6 doi (DE-627)DOAJ046777075 (DE-599)DOAJa43186bb4cd346d8948e060ed50b9538 DE-627 ger DE-627 rakwb eng QH426-470 Min-Wu Chao verfasserin aut Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Pancreatic cancer MPT0E028 MEK inhibitor EGFR K-Ras status Medicine R Genetics Li-Hsun Chang verfasserin aut Huang-Ju Tu verfasserin aut Chao-Di Chang verfasserin aut Mei-Jung Lai verfasserin aut Yi-Ying Chen verfasserin aut Jing-Ping Liou verfasserin aut Che-Ming Teng verfasserin aut Shiow-Lin Pan verfasserin aut In Clinical Epigenetics 11(2019), 1, Seite 14 volume:11 year:2019 number:1 pages:14 https://doi.org/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/article/a43186bb4cd346d8948e060ed50b9538 kostenfrei http://link.springer.com/article/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/toc/1868-7075 Journal toc kostenfrei https://doaj.org/toc/1868-7083 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 11 2019 1 14 |
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10.1186/s13148-019-0681-6 doi (DE-627)DOAJ046777075 (DE-599)DOAJa43186bb4cd346d8948e060ed50b9538 DE-627 ger DE-627 rakwb eng QH426-470 Min-Wu Chao verfasserin aut Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Pancreatic cancer MPT0E028 MEK inhibitor EGFR K-Ras status Medicine R Genetics Li-Hsun Chang verfasserin aut Huang-Ju Tu verfasserin aut Chao-Di Chang verfasserin aut Mei-Jung Lai verfasserin aut Yi-Ying Chen verfasserin aut Jing-Ping Liou verfasserin aut Che-Ming Teng verfasserin aut Shiow-Lin Pan verfasserin aut In Clinical Epigenetics 11(2019), 1, Seite 14 volume:11 year:2019 number:1 pages:14 https://doi.org/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/article/a43186bb4cd346d8948e060ed50b9538 kostenfrei http://link.springer.com/article/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/toc/1868-7075 Journal toc kostenfrei https://doaj.org/toc/1868-7083 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 11 2019 1 14 |
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10.1186/s13148-019-0681-6 doi (DE-627)DOAJ046777075 (DE-599)DOAJa43186bb4cd346d8948e060ed50b9538 DE-627 ger DE-627 rakwb eng QH426-470 Min-Wu Chao verfasserin aut Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Pancreatic cancer MPT0E028 MEK inhibitor EGFR K-Ras status Medicine R Genetics Li-Hsun Chang verfasserin aut Huang-Ju Tu verfasserin aut Chao-Di Chang verfasserin aut Mei-Jung Lai verfasserin aut Yi-Ying Chen verfasserin aut Jing-Ping Liou verfasserin aut Che-Ming Teng verfasserin aut Shiow-Lin Pan verfasserin aut In Clinical Epigenetics 11(2019), 1, Seite 14 volume:11 year:2019 number:1 pages:14 https://doi.org/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/article/a43186bb4cd346d8948e060ed50b9538 kostenfrei http://link.springer.com/article/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/toc/1868-7075 Journal toc kostenfrei https://doaj.org/toc/1868-7083 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 11 2019 1 14 |
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10.1186/s13148-019-0681-6 doi (DE-627)DOAJ046777075 (DE-599)DOAJa43186bb4cd346d8948e060ed50b9538 DE-627 ger DE-627 rakwb eng QH426-470 Min-Wu Chao verfasserin aut Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Pancreatic cancer MPT0E028 MEK inhibitor EGFR K-Ras status Medicine R Genetics Li-Hsun Chang verfasserin aut Huang-Ju Tu verfasserin aut Chao-Di Chang verfasserin aut Mei-Jung Lai verfasserin aut Yi-Ying Chen verfasserin aut Jing-Ping Liou verfasserin aut Che-Ming Teng verfasserin aut Shiow-Lin Pan verfasserin aut In Clinical Epigenetics 11(2019), 1, Seite 14 volume:11 year:2019 number:1 pages:14 https://doi.org/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/article/a43186bb4cd346d8948e060ed50b9538 kostenfrei http://link.springer.com/article/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/toc/1868-7075 Journal toc kostenfrei https://doaj.org/toc/1868-7083 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 11 2019 1 14 |
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10.1186/s13148-019-0681-6 doi (DE-627)DOAJ046777075 (DE-599)DOAJa43186bb4cd346d8948e060ed50b9538 DE-627 ger DE-627 rakwb eng QH426-470 Min-Wu Chao verfasserin aut Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. Pancreatic cancer MPT0E028 MEK inhibitor EGFR K-Ras status Medicine R Genetics Li-Hsun Chang verfasserin aut Huang-Ju Tu verfasserin aut Chao-Di Chang verfasserin aut Mei-Jung Lai verfasserin aut Yi-Ying Chen verfasserin aut Jing-Ping Liou verfasserin aut Che-Ming Teng verfasserin aut Shiow-Lin Pan verfasserin aut In Clinical Epigenetics 11(2019), 1, Seite 14 volume:11 year:2019 number:1 pages:14 https://doi.org/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/article/a43186bb4cd346d8948e060ed50b9538 kostenfrei http://link.springer.com/article/10.1186/s13148-019-0681-6 kostenfrei https://doaj.org/toc/1868-7075 Journal toc kostenfrei https://doaj.org/toc/1868-7083 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 11 2019 1 14 |
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However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. 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Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status |
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Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. |
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Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. |
| abstract_unstemmed |
Abstract Background Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. Methods The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. Results The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. Conclusions The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status. |
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