scholarly journals 8-Azaadenosine and 8-Chloroadenosine are not Selective Inhibitors of ADAR

2021 ◽  
Vol 1 (2) ◽  
pp. 56-64
Author(s):  
Kyle A. Cottrell ◽  
Luisangely Soto-Torres ◽  
Michael G. Dizon ◽  
Jason D. Weber
Keyword(s):  
Small Molecules ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Target ◽  
Cancer Cell Lines ◽  
Type I ◽  
Selective Inhibitors ◽  
Inhibition Of Proliferation ◽  
Translational Repressor ◽  
Multiple Cancers

The RNA editing enzyme ADAR is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in double-stranded RNAs. Loss of ADAR in some cancer cell lines causes activation of the type I IFN pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA-approved inhibitors of ADAR. Two small molecules have been previously shown to inhibit ADAR or reduce its expression: 8-azaadenosine and 8-chloroadenosine. Here we show that neither molecule is a selective inhibitor of ADAR. Both 8-azaadenosine and 8-chloroadenosine show similar toxicity to ADAR-dependent and -independent cancer cell lines. Furthermore, the toxicity of both small molecules is comparable between cell lines with either knockdown or overexpression of ADAR, and cells with unperturbed ADAR expression. Treatment with neither molecule causes activation of PKR. Finally, treatment with either molecule has no effect on A-to-I editing of multiple ADAR substrates. Together, these data show that 8-azaadenosine and 8-chloroadenosine are not suitable small molecules for therapies that require selective inhibition of ADAR, and neither should be used in preclinical studies as ADAR inhibitors. Significance: ADAR is a good therapeutic target for multiple cancers; neither 8-chloroadenosine nor 8-azaadenosine are selective inhibitors of ADAR.

scholarly journals 8-azaadenosine and 8-chloroadenosine are not selective inhibitors of ADAR

2021 ◽  
Author(s):  
Kyle A Cottrell ◽  
Luisangely Soto Torres ◽  
Jason D Weber
Keyword(s):  
Small Molecules ◽  
Cell Lines ◽  
Cancer Cell ◽  
Selective Inhibition ◽  
Cancer Cell Lines ◽  
Type I ◽  
Inhibition Of Proliferation ◽  
Translational Repressor ◽  
Attractive Therapeutic Target ◽  
Interferon Pathway

The RNA editing enzyme ADAR, is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in dsRNAs. Loss of ADAR in some cancer cell lines causes activation of the type I interferon pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA approved inhibitors of ADAR. Two small molecules have been previously described as inhibitors of ADAR: 8-azaadenosine and 8-chloroadenosine. Here we show that neither molecule is a selective inhibitor of ADAR. Both 8-azaadenosine and 8-chloroadenosine show similar toxicity to ADAR-dependent and independent cancer cell lines. Furthermore, the toxicity of both small molecules is comparable between cell lines with knockdown of ADAR and cells with unperturbed ADAR expression. Treatment with neither molecule causes activation of PKR. Finally, treatment with either molecule has no effect on A-to-I editing of an ADAR substrate. Together these data show that 8-azaadenosine and 8-chloroadenosine are not suitable small molecules for therapies that require selective inhibition of ADAR, and neither should be used in preclinical studies as ADAR inhibitors.

scholarly journals A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition

2008 ◽  
Vol 415 (1) ◽  
pp. 97-110 ◽  
Author(s):  
Neil E. Torbett ◽  
Antonio Luna-Moran ◽  
Zachary A. Knight ◽  
Andrew Houk ◽  
Mark Moasser ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Therapeutics ◽  
Cancer Cell Lines ◽  
Genetic Alterations ◽  
Breast Cancer Cell Lines ◽  
Selective Inhibitors

The PI3K (phosphoinositide 3-kinase) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small-molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we have demonstrated that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110α inhibitors were generally effective in inhibiting the phosphorylation of PKB (protein kinase B)/Akt and S6, two downstream components of PI3K signalling, in most cell lines examined. In contrast, p110β-selective inhibitors only reduced PKB/Akt phosphorylation in PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing cell-cycle arrest in the G1 phase, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell-cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signalling pathways. Taken together, our data indicate that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts.

scholarly journals Type I interferons induce autophagy in certain human cancer cell lines

Autophagy ◽  
2013 ◽  
Vol 9 (5) ◽  
pp. 683-696 ◽  
Author(s):  
Hana Schmeisser ◽  
Samuel B. Fey ◽  
Julie Horowitz ◽  
Elizabeth R. Fischer ◽  
Corey A. Balinsky ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Type I Interferons ◽  
Type I ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

Abstract 1678: Visualization of thymidine kinase 1 on the surface of cancer cell lines: A potential diagnostic marker and therapeutic target

2011 ◽  
Author(s):  
Robert A. Whitehurst ◽  
Dagoberto Estevez ◽  
Daniel W. Sharp ◽  
Melissa M. Alegre ◽  
Richard A. Robison ◽  
...  
Keyword(s):  
Thymidine Kinase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Target ◽  
Diagnostic Marker ◽  
Cancer Cell Lines ◽  
Thymidine Kinase 1

scholarly journals Role of secreted type I collagen derived from stromal cells in two breast cancer cell lines

2014 ◽  
Vol 8 (2) ◽  
pp. 507-512 ◽  
Author(s):  
SUNG HOON KIM ◽  
HYE YOON LEE ◽  
SEUNG PIL JUNG ◽  
SANGMIN KIM ◽  
JEONG EON LEE ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Stromal Cells ◽  
Type I Collagen ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Type I

scholarly journals Detection of Intracellular Granularity Induction in Prostate Cancer Cell Lines by Small Molecules Using the HyperCyt® High-Throughput Flow Cytometry System

2009 ◽  
Vol 14 (6) ◽  
pp. 596-609 ◽  
Author(s):  
Mark K. Haynes ◽  
J. Jacob Strouse ◽  
Anna Waller ◽  
Andrei Leitao ◽  
Ramona F. Curpan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Flow Cytometry ◽  
Small Molecules ◽  
Cell Lines ◽  
Cancer Cell ◽  
High Throughput ◽  
Prostate Cancer Cell ◽  
Cancer Cell Lines ◽  
Phenotypic Change ◽  
Prostate Cancer Cell Lines

Prostate cancer is a leading cause of death among men due to the limited number of treatment strategies available for advanced disease. Discovery of effective chemotherapeutics involves the identification of agents that inhibit cancer cell growth. Increases in intracellular granularity have been observed during physiological processes that include senescence, apoptosis, and autophagy, making this phenotypic change a useful marker for identifying small molecules that induce cellular growth arrest or death. In this regard, epithelial-derived cancer cell lines appear uniquely susceptible to increased intracellular granularity following exposure to chemotherapeutics. We have established a novel flow cytometry approach that detects increases in side light scatter in response to morphological changes associated with intracellular granularity in the androgen-sensitive LNCaP and androgen-independent PC3 human prostate cancer cell lines. A cell-based assay was developed to screen for small molecule inducers of intracellular granularity using the HyperCyt® high-throughput flow cytometry platform. Validation was performed using the Prestwick Chemical Library, where known modulators of LNCaP intracellular granularity, such as testosterone, were identified. Nonandrogenic inducers of granularity were also detected. A further screen of ~25,000 small molecules led to the identification of a class of aryl-oxazoles that increased intracellular granularity in both cell lines, often leading to cell death. The most potent agents exhibited submicromolar efficacy in LNCaP and PC3 cells. ( Journal of Biomolecular Screening. 2009:596-609)

Synthesis of indole based novel small molecules and their in vitro anti-proliferative effects on various cancer cell lines

2014 ◽  
Vol 55 (4) ◽  
pp. 921-926 ◽  
Author(s):  
Balakrishna Dulla ◽  
E. Sailaja ◽  
Upendar Reddy CH ◽  
Madhu Aeluri ◽  
Arunasree M. Kalle ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines

scholarly journals Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis

2020 ◽  
Author(s):  
Laura Ducimetière ◽  
Giulia Lucchiari ◽  
Gioana Litscher ◽  
Marc Nater ◽  
Laura Heeb ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Nk Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Great Promise ◽  
Type I ◽  
Metastatic Niche

SUMMARYThe liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and non-redundant action of two innate lymphocyte subpopulations, conventional NK cells (cNKs) and tissue-resident type I Innate Lymphoid Cells (trILC1s), is essential for anti-metastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 control metastatic seeding, whereas cNKs restrain outgrowth. The antimetastatic activity of cNKs is regulated in a tumor type-specific fashion. Thereby, individual cancer cell lines orchestrate the emergence of cNK subsets with unique phenotypic and functional traits. Understanding cancer-cell- as well as innate-cell-intrinsic factors will allow the exploitation of hepatic innate cells for development of novel cancer therapies.SignificanceInnate lymphoid cells hold great promise for the treatment of metastases. Development of effective therapies based on these versatile immune cells, however, is hampered by our limited knowledge of their behavior in the metastatic niche. Here, we describe that defense against liver metastasis requires the collaboration between two innate lymphocyte subsets, conventional NK cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s). We show that different cancers generate their own particular metastatic niche inducing specific changes in cNKs and trILC1s. Further, we uncover specific cNK subsets that can be manipulated to improve their anti-metastatic potential. Our work contributes to understanding how cancer-specific factors and hepatic innate lymphocytes exert mutual influence and how this can be exploited for therapeutic purposes.HighlightscNKs and trILC1s collaborate to control hepatic metastasistrILC1s restrict seeding and cNKs control outgrowth of cancer cells in the liverIndividual cancer cell lines orchestrate a distinct metastatic nicheThe metastatic niche dictates the phenotype and function of cNKs

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