CHIR-124, a Novel Potent Inhibitor of Chk1, Potentiates the Cytotoxicity of Topoisomerase I Poisons In vitro and In vivo

Abstract Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.

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A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys

Bone ◽

10.1016/j.bone.2006.07.015 ◽

2007 ◽

Vol 40 (1) ◽

pp. 122-131 ◽

Cited By ~ 95

Author(s):

S. Kumar ◽

L. Dare ◽

J.A. Vasko-Moser ◽

I.E. James ◽

S.M. Blake ◽

...

Keyword(s):

Bone Resorption ◽

Bone Turnover ◽

Potent Inhibitor ◽

Cathepsin K

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Topoisomerase I involvement in illegitimate recombination in Saccharomyces cerevisiae.

Molecular and Cellular Biology ◽

10.1128/mcb.16.4.1805 ◽

1996 ◽

Vol 16 (4) ◽

pp. 1805-1812 ◽

Cited By ~ 58

Author(s):

J Zhu ◽

R H Schiestl

Keyword(s):

Saccharomyces Cerevisiae ◽

Chromosome Aberrations ◽

Topoisomerase I ◽

Wild Type Strain ◽

Hot Spot ◽

Illegitimate Recombination ◽

Wild Type ◽

Yeast Saccharomyces Cerevisiae

Chromosome aberrations may cause cancer and many heritable diseases. Topoisomerase I has been suspected of causing chromosome aberrations by mediating illegitimate recombination. The effects of deletion and of overexpression of the topoisomerase I gene on illegitimate recombination in the yeast Saccharomyces cerevisiae have been studied. Yeast transformations were carried out with DNA fragments that did not have any homology to the genomic DNA. The frequency of illegitimate integration was 6- to 12-fold increased in a strain overexpressing topoisomerase I compared with that in isogenic control strains. Hot spot sequences [(G/C)(A/T)T] for illegitimate integration target sites accounted for the majority of the additional events after overexpression of topoisomerase I. These hot spot sequences correspond to sequences previously identified in vitro as topoisomerase I preferred cleavage sequences in other organisms. Furthermore, such hot spot sequences were found in 44% of the integration events present in the TOP1 wild-type strain and at a significantly lower frequency in the top1delta strain. Our results provide in vivo evidence that a general eukaryotic topoisomerase I enzyme nicks DNA and ligates nonhomologous ends, leading to illegitimate recombination.

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Interrogation of SLFN11 in pediatric sarcomas uncovers an unexpected biological role and a novel therapeutic approach to overcoming resistance to replicative stress

10.1101/2020.11.05.370155 ◽

2020 ◽

Author(s):

Jessica Gartrell ◽

Marcia Mellado-Largarde ◽

Nancy E. Martinez ◽

Michael R. Clay ◽

Armita Bahrami ◽

...

Keyword(s):

Tumor Growth ◽

Topoisomerase I ◽

Parp Inhibitor ◽

Selective Inhibition ◽

Common Mechanism ◽

Variable Response ◽

Replicative Stress ◽

Pediatric Sarcomas

AbstractPediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress, and SLFN11 gene silencing has been implicated as a common mechanism of drug resistance in tumors in adults. We found SLFN11 to be widely expressed in our cohort of pediatric sarcomas. In sarcoma cell lines, protein expression strongly correlated with response to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN), with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, SLFN11 expression was not associated with favorable outcomes in a retrospective analysis of our patient cohort; instead, the protein was retained and promoted tumor growth and evasion. Furthermore, we show that pediatric sarcomas develop resistance to TAL and IRN through impaired intrinsic apoptosis, and that resistance can be reversed by selective inhibition of BCL-XL.Statement of SignificanceThe role of SLFN11 in pediatric sarcomas has not been thoroughly explored. In contrast to its activity in adult tumors, SLFN11 did not predict favorable outcomes in pediatric patients, was not silenced, and promoted tumor growth. Resistance to replicative stress in SLFN11-expressing sarcomas was reversed by selective inhibition of BCL-XL.

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TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis

Endocrine Related Cancer ◽

10.1530/erc-17-0058 ◽

2017 ◽

Vol 24 (11) ◽

pp. 565-578 ◽

Cited By ~ 7

Author(s):

Hongqiang Wang ◽

Rui Zhou ◽

Li Sun ◽

Jianling Xia ◽

Xuchun Yang ◽

...

Keyword(s):

Cancer Progression ◽

Topoisomerase I ◽

Target Genes ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Migration And Invasion ◽

Glucose Transporter 1 ◽

Mesenchymal Transition

Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.

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Discovery of a novel anti-cancer agent targeting both topoisomerase I and II in hepatocellular carcinoma Hep 3B cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde

Journal of Drug Targeting ◽

10.3109/1061186x.2015.1132221 ◽

2016 ◽

Vol 24 (7) ◽

pp. 624-634 ◽

Cited By ~ 6

Author(s):

Daw-Shyong Perng ◽

Yu-Hsin Tsai ◽

Jonathan Cherng ◽

Chih-Wei Kuo ◽

Chih-Chung Shiao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Topoisomerase I ◽

Anti Cancer ◽

Cancer Agent

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4-Methoxydalbergione is a potent inhibitor of human astroglioma U87 cells in vitro and in vivo

Acta Pharmacologica Sinica ◽

10.1038/s41401-020-00560-w ◽

2020 ◽

Author(s):

Ran Li ◽

Chang-qiong Xu ◽

Jian-xin Shen ◽

Qiu-yun Ren ◽

Di-ling Chen ◽

...

Keyword(s):

Potent Inhibitor ◽

U87 Cells

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Regulation of peripheral lipogenesis by glucagon. Inability of the hormone to inhibit lipogenesis in rat mammary acini in vitro in the presence or absence of agents which alter its effects on adipocytes

Biochemical Journal ◽

10.1042/bj2170743 ◽

1984 ◽

Vol 217 (3) ◽

pp. 743-749 ◽

Cited By ~ 19

Author(s):

N A Robson ◽

R A Clegg ◽

V A Zammit

Keyword(s):

Concentration Ratio ◽

Response Curve ◽

Potent Inhibitor ◽

Specific Binding ◽

Insulin Dose ◽

Mammary Glands ◽

Key Steps ◽

Glucagon Concentration

The rate of lipogenesis in acini isolated from mammary glands of mid-lactating rats was studied by measuring the rate of incorporation of 3H from 3H2O into total lipid and fatty acids, with glucose as substrate. Glucagon did not affect the rate of lipogenesis in acini. Glucagon did not antagonize the maximal stimulatory effect of insulin, nor did it alter the insulin dose-response curve. Theophylline, at concentrations up to 20 mM, was a potent inhibitor of lipogenesis in acini. Glucagon did not augment the degree of inhibition of lipogenesis induced by 5 mM-theophylline. The results suggest that mammary-gland acini do not respond to glucagon in vitro under conditions in which the hormone induces inhibition of lipogenesis (the present paper) and of individual key steps in the lipogenic pathway in adipocytes [Zammit & Corstorphine (1982) Biochem. J. 208, 783-788; Green (1983) Biochem. J. 212, 189-195]. In agreement with these observations, we could detect only a minimal degree of specific binding of 125I-labelled glucagon to acini which bound insulin normally. This difference in responsiveness of mammary and adipose cell preparations in vitro to glucagon suggests that the two tissues may be differentially responsive to changes in the circulating insulin/glucagon concentration ratio in vivo. The significance of these findings for the regulation of substrate utilization for lipogenesis in the two tissues during lactation is discussed.

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