Pharmacological induction of translational readthrough of nonsense mutations in the retinoblastoma (RB1) gene.

The retinoblastoma protein (Rb) is encoded by the RB1 tumor suppressor gene. Inactivation of RB1 by inherited or somatic mutation occurs in retinoblastoma and various other types of tumors. A significant fraction (25.

Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant and .

The and tumour suppressor genes are inactivated by nonsense mutations in a significant fraction of human tumours. nonsense mutatant tumours account for approximately one million new cancer cases per year worldwide. We have screened chemical libraries with the aim of identifying compounds that induce translational readthrough and expression of full-length p53 protein in cells with nonsense mutation in this gene.

Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine.

TP53 nonsense mutations in cancer produce truncated inactive p53 protein. We show that 5-FU metabolite 5-Fluorouridine (FUr) induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53. Ribosome profiling visualized translational readthrough at the R213X premature stop codon and demonstrated that FUr-induced readthrough is less permissive for canonical stop codon readthrough compared to aminoglycoside G418.

Ipidacrine (Axamon), A Reversible Cholinesterase Inhibitor, Improves Erectile Function in Male Rats With Diabetes Mellitus-Induced Erectile Dysfunction.

Background: Management of diabetes mellitus-induced erectile dysfunction (DMED) is challenging because of its insufficient responses to phosphodiesterase type 5 inhibitors.

Aim: To compare the effects of ipidacrine, a reversible cholinesterase inhibitor, and sildenafil on DMED in a rat model of streptozotocin (STZ)-induced diabetes.

Methods: Erectile dysfunction (ED) caused by STZ-induced diabetes mellitus was modeled in adult male Wistar rats, which were randomized to 4 groups: untreated diabetic rats, sildenafil (5 mg/kg), ipidacrine (3.

Optimization of application schedule of camphecene, a novel anti-influenza compound, based on its pharmacokinetic characteristics.

Due to high variability and rapid life cycle, influenza virus is able to develop drug resistance against direct-acting antivirals. Development of novel virus-in113039hibiting drugs is therefore important goal. Previously, we identified camphor derivative, camphecene, as an effective anti-influenza compound.

Quantitative determination of new anti-inflammatory drug indomenthyl and its metabolite in rabbit plasma by HPLC-MS/MS.

: Indomenthyl is an innovative anti-inflammatory drug with a high analgesic activity. Indomenthyl releases indomethacin under the influence of neutrophil esterases in the inflammation focus. /: This research is aimed at developing a highly sensitive method for the quantitative determination of indomenthyl and its active metabolite indomethacin in rabbit plasma by HPLC-MS/MS.

Assessing the natural and anthropogenic radionuclide activities of the Pechora River estuary: Bottom sediments and water (Arctic Ocean Basin).

This paper studies the activity of natural and technogenic radionuclides in bottom sediments and surface water of the Pechora River estuary, which is the largest Arctic river within the European part of Russia. The relevance of conducting radioecological studies of this region is associated with active oil and gas activities in the Pechora basin and the presence of potential sources of radiation hazard. The average activities of Cs, Ra, Th, and K in bottom sediments were 0.

A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS).

Correction: APR-246 reactivates mutant p53 by targeting cysteines 124 and 277.

Since publication of this article, the authors have noticed that there was an error in Fig. 1d, third panel from left, "R273H + 200 μM MQ-H" should be "R273H + 200 μM MQ". Our corrections do not affect the original conclusions of this paper.

p53 as a hub in cellular redox regulation and therapeutic target in cancer.

The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells.

TP53 is the most frequently mutated gene in human cancer and thus an attractive target for novel cancer therapy. Several compounds that can reactive mutant p53 protein have been identified. APR-246 is currently being tested in a phase II clinical trial in high-grade serous ovarian cancer.

Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246.

The tumor suppressor p53 is commonly inactivated in human tumors, allowing evasion of p53-dependent apoptosis and tumor progression. The small molecule APR-246 (PRIMA-1) can reactive mutant p53 in tumor cells and trigger cell death by apoptosis. The thioredoxin (Trx) and glutaredoxin (Grx) systems are important as antioxidants for maintaining cellular redox balance and providing electrons for thiol-dependent reactions like those catalyzed by ribonucleotide reductase and peroxiredoxins (Prxs).

Needling With 5-Fluorouracil (5-FU) After XEN Gel Stent Implantation: 6-Month Outcomes.

Purpose: The purpose of this study was to evaluate frequency, safety, and efficacy of needling in patients that underwent XEN Gel Stent implantation.

Methods: Retrospective case review of 19 eyes of 57 consecutive patients (61 eyes) with primary open-angle glaucoma or pseudoexfoliative glaucoma that previously underwent implantation of XEN45 alone or in combination with cataract surgery followed by needling procedure with 5-FU. Success was defined at 2 IOP levels: ≤21 mm Hg and ≤15 mm Hg, with or without additional glaucoma medications.

Role of Thiol Reactivity for Targeting Mutant p53.

Reactivation of mutant p53 has emerged as a promising approach for cancer therapy. Recent studies have identified several mutant p53-reactivating compounds that target thiol groups in mutant p53. Here we have investigated the relationship between thiol reactivity, p53 thermostabilization, mutant p53 refolding, mutant p53-dependent growth suppression, and induction of cell death.

APR-246 reactivates mutant p53 by targeting cysteines 124 and 277.

The TP53 tumor suppressor gene is frequently inactivated in human tumors by missense mutations in the DNA binding domain. TP53 mutations lead to protein unfolding, decreased thermostability and loss of DNA binding and transcription factor function. Pharmacological targeting of mutant p53 to restore its tumor suppressor function is a promising strategy for cancer therapy.

Synergistic Rescue of Nonsense Mutant Tumor Suppressor p53 by Combination Treatment with Aminoglycosides and Mdm2 Inhibitors.

The tumor suppressor gene is inactivated by mutation in a large fraction of human tumors. Around 10% of mutations are nonsense mutations that lead to premature termination of translation and expression of truncated unstable and non-functional p53 protein. Aminoglycosides G418 (geneticin) and gentamicin have been shown to induce translational readthrough and expression of full-length p53.

Radioprotective and radiomitigative effects of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, in two mouse strains exposed to total body irradiation.

Purpose: There remains an unmet medical need for radioprotective and mitigative agents. BP-C2 is a novel lignin-derived polyphenolic composition with ammonium molybdate, developed as radioprotector/radiomitigator.

Objectives: The present study evaluated BP-C2 for the mitigation of acute radiation syndrome (ARS).

Targeting mutant p53 for efficient cancer therapy.

The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression.

Results and prospects of development of new polyphenolic drugs for cancer patients.

The conference "Results and prospects of development of new polyphenolic drugs for cancer patients" took place at the N.N. Petrov National Medical Research Center of Oncology (PNMRCO) on May 31, 2017, and gathered researchers involved in development and evaluation of medicinal products based on the novel lignin-derived soluble polyphenolic polymer BP-Cx-1.

Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death.

Drug resistance is a major problem in cancer therapy. A growing body of evidence demonstrates that the tumor microenvironment, including cancer-associated fibroblasts (CAFs), can modulate drug sensitivity in tumor cells. We examined the effect of primary human CAFs on p53 induction and cell viability in prostate cancer cells on treatment with chemotherapeutic drugs.