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Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression.
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Abstract:
:Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.
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Theranostics
THERANOSTICS
| 最新影响因子：11.6 | 期刊ISSN：1838-7640 | CiteScore：8.7 |
| 出版周期： | 是否OA：YES | 出版年份：2011 |
期刊官方网址：http://www.thno.org/
| 自引率：7.70% | 研究方向：MEDICINE, RESEARCH & EXPERIMENTAL- |
| 出版地区：AUSTRALIA |
SCI期刊coverage：Science Citation Index Expanded（科学引文索引扩展）
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Theranostics 期刊简介
英文简介：
The aim of Theranostics is to provide a forum for the exchange of clinical and scientific information for the diagnostic and therapeutic molecular and nano medicine community and allied professions involved in the efforts of integrating molecular imaging and molecular therapy. Theranostics is a multidisciplinary journal that publishes innovative and original research articles reflecting fields of in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor, nanobiosensor and bioelectronics, system biology and translational medicine, point-of-care and personalized medicine. A broad spectrum of biomedical research that can be applied to future theranostic applications is encouraged. In addition to primary research, Theranostics also publishes reviews, news, and commentary to understand and bridge the gap among the laboratory, clinic, and biotechnology industries. Papers in the journal are rigorously peer-reviewed.
中文简介：（来自Google、百度翻译）
Theranostics的目的是为诊断和治疗分子和纳米医学社区以及相关专业提供一个交流临床和科学信息的论坛，这些专业致力于将分子成像和分子治疗结合起来。Theranostics是一份多学科期刊，发表创新和原创的研究文章，反映了体外诊断和预测、体内分子成像、分子治疗、图像引导治疗、生物传感器、纳米生物传感器和生物电子学、系统生物学和转化医学、定点医疗和个性化医疗等领域。鼓励广泛的生物医学研究，可应用于未来的theranostic应用。除了初级研究，Theranostics还出版评论、新闻和评论，以了解和弥合实验室、临床和生物技术行业之间的差距。杂志上的论文都经过严格的同行评审。
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Theranostics 期刊中科院评价数据
最新中科院分区
| 大类(学科) | 小类(学科) | 学科排名 |
| 医学 |
MEDICINE, RESEARCH & EXPERIMENTAL (医学：研究与实验) 2区 |
8/133 |
最新公布的期刊年发文量
| 年度总发文量 | 年度论文发表量 | 年度综述发表量 |
| 353 | 323 | 30 |
总被引频次：8769
特征因子：0.020270
影响因子趋势图
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Theranostics 期刊CiteScore评价数据
最新CiteScore值
8.7
=
引文计数(2018)
文献(2015-2017)
=
3480次引用
400篇文献
文献总数（2014-2016）：400
被引比率：96%
SJR：2.515
SCLmago期刊等级衡量经过加权后的期刊受引用次数，引用次数的加权值由施引期刊的学科领域和声望(SJR)决定。
SNIP：1.791
每篇文章中来源出版物的标准化影响将实际受引用情况对照期刊所属学科领域中预期的受引用情况进行衡量。
CiteScore排名
| 序号 | 类别 | 排名 | 百分位 |
| 1 |
大类(学科)：Medicine
小类(学科)：Medicine (miscellaneous)
|
#4/189
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|
|
| 2 |
大类(学科)：Pharmacology, Toxicology and Pharmaceutics
小类(学科)：Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
|
#1/22
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|
|
CiteScore趋势图
Scopus涵盖范围
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