Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function

AbstractDespite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.

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Inhibition of histone acetyltranserase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a novel gain of function

10.1101/2020.04.10.028217 ◽

2020 ◽

Author(s):

Manish Kumar ◽

David Molkentine ◽

Jessica Molkentine ◽

Kathleen Bridges ◽

Tongxin Xie ◽

...

Keyword(s):

Homologous Recombination ◽

Histone Acetyltransferase ◽

Treatment Resistance ◽

Histone Acetyltransferases ◽

Clinical Use ◽

Gain Of Function ◽

Chemical Inhibition ◽

Radiation Sensitizers

AbstractDespite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiation sensitizers for clinical use. We performed in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identified the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirmed this phenomenon was due to repression of homologous recombination following DNA damage and can be reproduced using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targets by HAT inhibition. Additionally, mutations in CREBBP/EP300 were associated with recurrence following radiation, in several squamous cell carcinoma cohorts. These findings represent both a novel mechanism of treatment resistance and the potential for genomically-driven treatment.

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Efficient In Vitro System of Homologous Recombination in Brome Mosaic Bromovirus

Journal of Virology ◽

10.1128/jvi.02447-05 ◽

2006 ◽

Vol 80 (12) ◽

pp. 6182-6187 ◽

Cited By ~ 14

Author(s):

Rafal Wierzchoslawski ◽

Jozef J. Bujarski

Keyword(s):

Homologous Recombination ◽

Recombination Frequency ◽

In Vivo Studies ◽

Rna Recombination ◽

In Vitro System ◽

Brome Mosaic Bromovirus ◽

Subgenomic Promoter

ABSTRACT Recent in vivo studies have revealed that the subgenomic promoter (sgp) in brome mosaic bromovirus (BMV) RNA3 supports frequent homologous recombination events (R. Wierzchoslawski, A. Dzianott, and J. Bujarski, J. Virol. 78:8552-8564, 2004). In this paper, we describe an sgp-driven in vitro system that supports efficient RNA3 crossovers. A 1:1 mixture of two (−)-sense RNA3 templates was copied with either a BMV replicase (RdRp) preparation or recombinant BMV protein 2a. The BMV replicase enzyme supported a lower recombination frequency than 2a, demonstrating a role of other viral and/or host factors. The described in vitro system will allow us to study the mechanism of homologous RNA recombination.

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Current pharmacological treatment of bladder hyperactivity

Urologia Journal ◽

10.1177/039156039606300405 ◽

1996 ◽

Vol 63 (4) ◽

pp. 441-444

Author(s):

P. Checchin ◽

G. Anselmo

Keyword(s):

Side Effects ◽

Pharmacological Treatment ◽

Bladder Capacity ◽

In Vivo Studies ◽

Clinical Effects ◽

Clinical Use ◽

Action Mechanism ◽

Drug Influence

Bladder hyperactivity is a serious pathology with a high clinical incidence. Various drugs have been used to try to inhibit involuntary detrusorial contractions and to increase bladder capacity. The authors describe the properties, action mechanism, clinical use and side effects of the main drugs analysed. Most of the data regarding drug influence on the vesico-urethral apparatus are obtained from “in vitro” or “in-vivo” studies on animals and therefore cannot always be related to the clinical effects that would occur in man. It is still difficult to find an “ideal” drug with high detrusor selectivity, due to both the lack of knowledge on neuro-mediators and the difficulty in identifying receptors and “action sites”.

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Laser Photobiomodulation (PBM)—A Possible New Frontier for the Treatment of Oral Cancer: A Review of In Vitro and In Vivo Studies

Healthcare ◽

10.3390/healthcare9020134 ◽

2021 ◽

Vol 9 (2) ◽

pp. 134

Author(s):

Alessandro Del Vecchio ◽

Gianluca Tenore ◽

Maria Clotilde Luzi ◽

Gaspare Palaia ◽

Ahmed Mohsen ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cancer ◽

Data Extraction ◽

In Vivo Studies ◽

Clinical Use ◽

Inclusion Criteria ◽

Beneficial Effects ◽

New Frontier

The treatment of oral squamous cell carcinoma (OSCC) is particularly complex due to its aggressive behavior, location, the patient’s age, and its spread at diagnosis. In recent years, photobiomodulation (PBM) has been introduced in different medical fields; however, its application, in patients suffering from OSCC for palliative support or to induce analgesia, has been hotly debated due to the possibility that the cell growth stimuli induced by PBM could lead to a worsening of the lesions. The aim of this study is to review the literature to observe the available data investigating the effect of PBM on cancer cells in vitro and in vivo. A review was conducted on the PubMed and Scopus databases. A total of twelve studies met the inclusion criteria and were therefore included for quality assessment and data extraction. The analysis showed that the clinical use of PBM is still only partially understood and is, therefore, controversial. Some authors stated that it could be contraindicated for clinical use in patients suffering from SCC, while others noted that it could have beneficial effects. According to the data that emerged from this review, it is possible to hypothesize that there are possibilities for PBM to play a beneficial role in treating cancer patients, but further evidence about its clinical efficacy and the identification of protocols and correct dosages is still needed.

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Chlorhexidine incorporated into the prosthesis as a treatment strategy for denture stomatitis

Revista Brasileira de Odontologia ◽

10.18363/rbo.v74n4.p.288 ◽

2017 ◽

Vol 74 (4) ◽

pp. 288 ◽

Cited By ~ 1

Author(s):

Marcela Mendes Medeiros Michelon ◽

Karina De Paula Lopes Campos ◽

Luciana Quintanilha Pires Fernandes ◽

Daniel De Moraes Telles ◽

Guaracilei Junior Maciel Vidigal

Keyword(s):

Candida Albicans ◽

Treatment Strategy ◽

In Vivo Studies ◽

Clinical Use ◽

Denture Stomatitis ◽

Advanced Search ◽

Patient Cooperation ◽

The Subject

Objective: to perform a literature review on the denture stomatitis (DS) treatment, in order to propose the incorporation of chlorhexidine into the denture as a treatment strategy for DS. Material and Methods: an advanced search was undertaken in MEDLINE/PubMed baseline from 1976 to 2016. Sixty-five papers were retrieved using the following keywords: chlorhexidine, denture stomatitis, denture relining. Of those, 35 papers were directly related to the subject and were therefore selected for a narrative review. Results: DS is an inflammatory reaction of multifactorial etiology, usually associated with Candida albicans and often observed in complete denture wearers. Most treatments rely on patient cooperation. Chlorhexidine (CHX) has antifungal activity and can be incorporated into denture lining materials without causing significant alterations in denture resin structure and without depending on patient compliance. Conclusion: according to the results of in vitro studies, CHX released from denture relining materials may be convenient to reduce denture biofilms and treat DS, but further in vivo studies are necessary to recommend clinical use.

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Anticancer Potential of Lichens’ Secondary Metabolites

Biomolecules ◽

10.3390/biom10010087 ◽

2020 ◽

Vol 10 (1) ◽

pp. 87 ◽

Cited By ~ 10

Author(s):

Zuzana Solárová ◽

Alena Liskova ◽

Marek Samec ◽

Peter Kubatka ◽

Dietrich Büsselberg ◽

...

Keyword(s):

Secondary Metabolites ◽

Biological Activities ◽

In Vivo Studies ◽

Clinical Use ◽

Anticancer Activities ◽

Cancer Management ◽

Anticancer Effects ◽

Lichen Metabolites

Lichens produce different classes of phenolic compounds, including anthraquinones, xanthones, dibenzofuranes, depsides and depsidones. Many of them have revealed effective biological activities such as antioxidant, antiviral, antibiotics, antifungal, and anticancer. Although no clinical study has been conducted yet, there are number of in vitro and in vivo studies demonstrating anticancer effects of lichen metabolites. The main goal of our work was to review most recent published papers dealing with anticancer activities of secondary metabolites of lichens and point out to their perspective clinical use in cancer management.

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Synthesis and Biochemical Evaluation of Baicalein Prodrugs

Pharmaceutics ◽

10.3390/pharmaceutics13091516 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1516

Author(s):

Sang-Hyun Son ◽

Jinhong Kang ◽

Myunghwan Ahn ◽

Soyeon Nam ◽

Yong Woo Jung ◽

...

Keyword(s):

Atopic Dermatitis ◽

Animal Studies ◽

Functional Group ◽

In Vivo Studies ◽

Clinical Use ◽

Plasma Exposure ◽

Pharmacological Activities ◽

Biochemical Evaluation

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid analog from Scutellaria baicalensis, possesses several pharmacological activities including antioxidant, antiproliferative, and anti-inflammatory activities. We previously reported that baicalein inhibits the thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) signaling pathways and can be used as an active ingredient in the treatment of asthma and atopic dermatitis. However, baicalein is rapidly metabolized to baicalin and baicalein-6-O-glucuronide in vivo, which limits its preclinical and clinical use. In this study, we designed, synthesized, and evaluated baicalein prodrugs that protect the OH group at the 7-position of the A ring in baicalein with the amino acid carbamate functional group. Comprehensive in vitro and in vivo studies identified compound 2 as a baicalein prodrug candidate that improved the plasma exposure of baicalein in mouse animal studies. Our results demonstrated that this prodrug approach could be further adopted to discover oral baicalein prodrugs.

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