NAHA, a Novel Hydroxamic Acid-Derivative, Inhibits Growth and Angiogenesis of Breast Cancer In Vitro and In Vivo

BACKGROUND: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitro-benzenesulfonyl)-amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. CONCLUSION: NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers

High-Definition DNA Methylation Profiles from Breast and Ovarian Carcinoma Cell Lines with Differing Doxorubicin Resistance

Acquired drug resistance represents a frequent obstacle which hampers efficient chemotherapy of cancers. The contribution of aberrant DNA methylation to the development of drug resistant tumor cells has gained increasing attention over the past decades. Hence, the objective of the presented study was to characterize DNA methylation changes which arise from treatment of tumor cells with the chemotherapeutic drug doxorubicin. DNA methylation levels from CpG islands (CGIs) linked to twenty-eight genes, whose expression levels had previously been shown to contribute to resistance against DNA double strand break inducing drugs or tumor progression in different cancer types were analyzed. High-definition DNA methylation profiles which consisted of methylation levels from 800 CpG sites mapping to CGIs around the transcription start sites of the selected genes were determined. In order to investigate the influence of CGI methylation on the expression of associated genes, their mRNA levels were investigated via qRT-PCR. It was shown that the employed method is suitable for providing highly accurate methylation profiles, comparable to those obtained via clone sequencing, the gold standard for high-definition DNA methylation studies. In breast carcinoma cells with acquired resistance against the double strand break inducing drug doxorubicin, changes in methylation of specific cytosines from CGIs linked to thirteen genes were detected. Moreover, similarities between methylation profiles obtained from breast and ovarian carcinoma cell lines with acquired doxorubicin resistance were found. The expression levels of a subset of analyzed genes were shown to be linked to the methylation levels of the analyzed CGIs. Our results provide detailed DNA methylation information from two separate model systems for acquired doxorubicin resistance and suggest the occurrence of similar methylation changes in both systems upon exposure to the drug

5-Aza-2′-deoxycytidine stress response and apoptosis in prostate cancer

While studying on epigenetic regulatory mechanisms (DNA methylation at C-5 of –CpG– cytosine and demethylation of methylated DNA) of certain genes (FAS, CLU, E-cadh, CD44, and Cav-1) associated with prostate cancer development and its better management, we noticed that the used in vivo dose of 5-aza-2′-deoxycytidine (5.0 to 10.0 nM, sufficient to inhibit DNA methyltransferase activity in vitro) helped in the transcription of various genes with known (steroid receptors, AR and ER; ER variants, CD44, CDH1, BRCA1, TGFβR1, MMP3, MMP9, and UPA) and unknown (DAZ and Y-chromosome specific) proteins and the respective cells remained healthy in culture. At a moderate dose (20 to 200 nM) of the inhibitor, cells remain growth arrested. Upon subsequent challenge with increased dose (0.5 to 5.0 μM) of the inhibitor, we observed that the cellular morphology was changing and led to death of the cells with progress of time. Analyses of DNA and anti-, pro-, and apoptotic factors of the affected cells revealed that the molecular events that went on are characteristics of programmed cell death (apoptosis)

Epigenetic regulation of prostate cancer

Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Orofacial viral infections--an update for clinicians

Orofacial viral infections may be less common but appear in different clinical forms. Often these infections get initially treated by antibiotics which obviously will have limited or no effect. The authors review the current concepts of orofacial viral infections, causative agents, their classification and clinical manifestations and a basis for treatment.Griffith Health, School of Dentistry and Oral HealthNo Full Tex

Efficacy and tolerability of short-course exclusive enteral nutrition as an adjunct to standard therapy in patients with acute severe ulcerative colitis

Background and Aim: Acute severe ulcerative colitis (ASUC) occurs in about 15–25% of patients with ulcerative colitis (UC). Intravenous corticosteroids remain the first-line therapy. However, about 30% of patients fail to respond to corticosteroids and will require medical rescue therapy or colectomy.1 A recent randomized controlled trial suggested that the adjunctive use of short-course exclusive enteral nutrition (EEN) for a period of 7 days in patients with ASUC was associated with lower rates of steroid failure compared with standard care.2 We aimed to determine the efficacy and tolerability of short-course EEN as an adjunct to standard therapy in our local cohort of patients with ASUC. Methods: We performed a retrospective analysis of patients presenting with ASUC, diagnosed using the Truelove and Witts criteria, who were treated with short-course EEN in addition to standard care between June 2022 and March 2023. Data collection included age, sex, distribution of UC, prior use of biologic agent, endoscopic Mayo score, fecal calprotectin level on admission, number requiring infliximab rescue therapy on Day 3, and number proceeding to colectomy during index admission. Outcome measures were tolerability of short-course EEN and its efficacy in preventing steroid failure, as defined by the Oxford criteria. Patients who declined EEN were excluded. Results: Fifteen patients were included in our study. The median age was 32 years (range, 18–78 years), and 60% were male. Most patients (73.3%) had pancolonic UC, with 26.7% already using a biologic agent. Eleven of the 15 patients had flexible sigmoidoscopy during admission, while three had colonoscopies within 1 week before presentation. One patient did not have an endoscopic assessment due to active COVID-19 infection. Half (53.3%) had an endoscopic Mayo score of 3, with 40% having an endoscopic Mayo score of 2. The median fecal calprotectin level on admission was 2300 μg/g (range, 240–7600 μg/g). Thirteen of 15 patients (86.7%) completed 7 days of EEN. One patient declined to continue EEN, and one discontinued due to vomiting, both on Day 3. Corticosteroid failures were recorded for two of 15 patients (13.3%), who required infliximab rescue therapy. Both had completed 7 days of EEN. No patient required colectomy. Conclusion: Our data indicate that short-course EEN in addition to standard care for these patients presenting with ASUC had a high degree of tolerability (86.7%) and lower rates of steroid failure than reported in the literature (13.3% vs 30%). A more robust prospective randomized controlled trial is required to further characterize the efficacy of EEN in patients with ASUC, as well as to determine optimal duration of therapy.No Full Tex