摘要
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.
原文 | 英語 |
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文章編號 | 85 |
頁(從 - 到) | 85 |
期刊 | Clinical Epigenetics |
卷 | 11 |
發行號 | 1 |
DOIs | |
出版狀態 | 已發佈 - 5月 29 2019 |
ASJC Scopus subject areas
- 分子生物學
- 遺傳學
- 發展生物學
- 遺傳學(臨床)
指紋
深入研究「Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status」主題。共同形成了獨特的指紋。資料集
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Additional file 5: of Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status
Chang, L.-H. (Contributor), Liou, J.-P. (Creator), Lai, M.-J. (Contributor), Chang, C.-D. (Contributor), Tu, H.-J. (Contributor), Chao, M.-W. (Contributor), Pan, S.-L. (Contributor), Chen, Y.-Y. (Creator) & Teng, C.-M. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.8202902.v1, https://doi.org/10.6084%2Fm9.figshare.8202902.v1
資料集: Dataset
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Additional file 1: of Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status
Chao, M.-W. (Contributor), Chang, L.-H. (Contributor), Tu, H.-J. (Contributor), Chang, C.-D. (Contributor), Lai, M.-J. (Contributor), Chen, Y.-Y. (Creator), Liou, J.-P. (Creator), Teng, C.-M. (Contributor) & Pan, S.-L. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.8202881.v1, https://springernature.figshare.com/articles/Additional_file_1_of_Combination_treatment_strategy_for_pancreatic_cancer_involving_the_novel_HDAC_inhibitor_MPT0E028_with_a_MEK_inhibitor_beyond_K-Ras_status/8202881/1
資料集: Dataset
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Additional file 3: of Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status
Chao, M.-W. (Contributor), Chang, L.-H. (Contributor), Tu, H.-J. (Contributor), Chang, C.-D. (Contributor), Lai, M.-J. (Contributor), Chen, Y.-Y. (Creator), Liou, J.-P. (Creator), Teng, C.-M. (Contributor) & Pan, S.-L. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.8202890.v1, https://springernature.figshare.com/articles/Additional_file_3_of_Combination_treatment_strategy_for_pancreatic_cancer_involving_the_novel_HDAC_inhibitor_MPT0E028_with_a_MEK_inhibitor_beyond_K-Ras_status/8202890/1
資料集: Dataset