Ascorbic acid (vitamin C) has been gaining attention as a potential treatment for human malignancies. Various experimental studies have shown the ability of pharmacological doses of vitamin C alone ...or in combinations with clinically used drugs to exert beneficial effects in various models of human cancers. Cytotoxicity of high doses of vitamin C in cancer cells appears to be related to excessive reactive oxygen species generation and the resulting suppression of the energy production via glycolysis. A hallmark of cancer cells is a strongly upregulated aerobic glycolysis, which elevates its relative importance as a source of ATP (Adenosine 5'-triphosphate). Aerobic glycolysis is maintained by a highly increased uptake of glucose, which is made possible by the upregulated expression of its transporters, such as GLUT-1, GLUT-3, and GLUT-4. These proteins can also transport the oxidized form of vitamin C, dehydroascorbate, permitting its preferential uptake by cancer cells with the subsequent depletion of critical cellular reducers as a result of ascorbate formation. Ascorbate also has a potential to affect other aspects of cancer cell metabolism due to its ability to promote reduction of iron(III) to iron(II) in numerous cellular metalloenzymes. Among iron-dependent dioxygenases, important targets for stimulation by vitamin C in cancer include prolyl hydroxylases targeting the hypoxia-inducible factors HIF-1/HIF-2 and histone and DNA demethylases. Altered metabolism of cancer cells by vitamin C can be beneficial by itself and promote activity of specific drugs.
Head and neck cancer is characterized by malignant tumors arising from the epithelium covering the upper aerodigestive tract, and the majority of these epithelial malignancies are squamous cell ...carcinomas (SCCs) of the oral cavity (OSCCs). The aim of the current work was to identify miRNAs regulated in OSCC cancerous tissue when compared to a healthy adjacent tissue and to verify the presence of the same miRNAs in the circulation of these patients. For that serum samples and biopsies of healthy and tumor tissues were collected from five patients diagnosed with OSCC of the oral cavity, RNA was extracted from these samples and microRNAs libraries were prepared and sequenced. A total 255 miRNAs were identified in tissue and 381 different miRNAs were identified in serum samples. When comparing the miRNA expression between tumor and healthy tissue we identified 48 miRNAs (25 down- and 23 up-regulated) that were differentially expressed (FDR < 0.05). From these 48 differentially expressed miRNAs in tissue, 30 miRNAs were also found in the serum of the same patients. hsa-miR-32-5p was up-regulated in tumor compared to healthy tissue in our study, and was previously shown to be up-regulated in the serum of OSCC patients. Therefore, this suggests that miRNAs can be used as potential non-invasive biomarkers of OSCC.
Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of ...PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine.
Fucoidans have been reported to exert anticancer effects with simultaneous low toxicity against healthy tissue. That correlation was observed in several cancer models, however, it has never been ...investigated in head and neck cancer before. To magnify the efficacy of conventional therapy, the administration of agents like fucoidan could be beneficial. The aim of this study was to evaluate the anticancer effect of
(FV) extract alone and with co-administration of cisplatin in head and neck squamous cell carcinoma (HNSCC) in vitro. MTT assay results revealed an FV-induced inhibition of proliferation in all tested cell lines (H103, FaDu, KB). Flow cytometric cell cycle analysis showed an FV-induced, dose-dependent arrest in either S/G2 phase (H103, FaDu) or G1 arrest (KB). Furthermore, a dose-dependent gain in apoptotic fraction was observed. Western blot analysis confirmed the induction of apoptosis. A significant dose-dependent increase in reactive oxygen species (ROS) production was revealed in the H103 cell line, while FaDu cells remained unresponsive. On the contrary, an HPV-positive cell line, KB, demonstrated a dose-dependent decrease in ROS synthesis. Moreover, fucoidan enhanced the response to cisplatin (synergistic effect) in all cell lines with the HPV-positive one (KB) being the most sensitive. These results have been confirmed by flow-cytometric apoptosis analysis. In conclusion, we confirmed that fucoidan exhibits anticancer properties against HNSCC, which are manifested by the induction of apoptosis, regulation of ROS production, cell cycle arrest, and inhibition of proliferation.
The pRb-E2F pathway is a critical point of regulation in the cell cycle and loss of control of the pathway is a hallmark of cancer. E2F1 is the major target through which pRb exerts its effects and ...arginine methylation by PRMT5 plays a key role in dictating E2F1 activity. Here we have explored the functional role of the PRMT5-E2F1 axis and highlight its influence on different aspects of cancer cell biology including viability, migration, invasion and adherence. Through a genome-wide expression analysis, we identified a distinct set of genes under the control of PRMT5 and E2F1, including some highly regulated genes, which influence cell migration, invasio and adherence through a PRMT5-dependent mechanism. Most significantly, a coincidence was apparent between the expression of PRMT5 and E2F1 in human tumours, and elevated levels of PRMT5 and E2F1 correlated with poor prognosis disease. Our results suggest a causal relationship between PRMT5 and E2F1 in driving the malignant phenotype and thereby highlight an important pathway for therapeutic intervention.
Aberrant protein acetylation is strongly linked to tumorigenesis, and modulating acetylation through targeting histone deacetylase (HDAC) with small‐molecule inhibitors has been the focus of clinical ...trials. However, clinical success on solid tumours, such as colorectal cancer (CRC), has been limited, in part because the cancer‐relevant mechanisms through which HDAC inhibitors act remain largely unknown. Here, we have explored, at the genome‐wide expression level, the effects of a novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up‐ and downregulated upon CXD101 treatment. Functional profiling of the expression data highlighted immune‐relevant concepts related to antigen processing and natural killer cell‐mediated cytotoxicity. Similar profiles were apparent when gene expression was investigated in murine colon26 CRC cells treated with CXD101. Significantly, these changes were also apparent in syngeneic colon26 tumours growing in vivo. The ability of CXD101 to affect immune‐relevant gene expression coincided with changes in the tumour microenvironment (TME), especially in the subgroups of CD4 and CD8 tumour‐infiltrating T lymphocytes. The altered TME reflected enhanced antitumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti‐PD‐1 and anti‐CTLA4. The ability of CXD101 to reinstate immune‐relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers.
CXD101 is a novel histone deacetylase inhibitor with potent antitumour activity. We find that CXD101 reinstates immune‐relevant gene expression in tumours, which includes major histocompatibility complex class I and class II genes. This enables CXD101 to enhance the activity of immune checkpoint therapies, such as anti‐PD‐1, on tumours that would otherwise be poorly responsive and coincides with increased T lymphocyte infiltration into the tumour microenvironment.
Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. These tumors originate from epithelial cells of the upper aerodigestive tract. HNSCC tumors in different ...regions can have significantly different molecular characteristics. While many microRNAs (miRNAs) have been found to be involved in the regulation of the carcinogenesis and pathogenesis of HNSCC, new HNSCC related miRNAs are still being discovered. The aim of this study was to explore potential miRNA biomarkers that can be used to diagnose HNSCC and prognose survival of HNSCC patients. For this purpose, we chose a panel of 12 miRNAs: miR-146a-5p, miR-449a, miR-126-5p, miR-34a-5p, miR-34b-5p, miR-34c-5p, miR-217-5p, miR-378c, miR-6510-3p, miR-96-5p, miR-149-5p, and miR-133a-5p. Expression of these miRNAs was measured in tumor tissue and neighboring healthy tissue collected from patients diagnosed with HNSCC (n = 79) in either the oral cavity, oropharynx, or larynx. We observed a pattern of differentially expressed miRNAs at each of these cancer locations. Our study showed that some of these miRNAs, separately or in combination, could serve as biomarkers distinguishing between healthy and tumor tissue, and their expression correlated with patients’ overall survival.
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of cancer and the third leading cause of cancer death with the lowest 5-year survival rate. Heterogeneity, difficulty in diagnosis, and ...rapid metastatic progression are the causes of high mortality in pancreatic cancer. Recent studies have shown that Protein arginine methyltransferase 5 (PRMT5) is overexpressed in pancreatic cancers, and these patients have a worse prognosis. Recently, PRMT5 as an anti-cancer target has gained considerable interest. In this study, we investigated whether inhibition of PRMT5 activity was synergistic with blockade of TGF-β1 signaling, which plays an important role in the construction of the desmoplastic matrix in pancreatic cancer and induces therapeutic vulnerability. Compared with T1-44, a selective inhibitor of PRMT5 activity, the combination of T1-44 with the TGF-β1 signaling inhibitor Vactosertib significantly reduced tumor size and surrounding tissue invasion and significantly improved long-term survival. RNA sequencing analysis of mouse tumors revealed that the combination of T1-44 and Vactosertib significantly altered the expression of genes involved in cancer progression, such as cell migration, extracellular matrix, and apoptotic processes. In particular, the expression of Btg2, known as a tumor suppressor factor in various cancers, was markedly induced by combination treatment. Ectopic overexpression of Btg2 inhibited the EMT response, blocking cell migration, and promoted cancer cell death. These data demonstrate that the combination therapy of T1-44 with Vactosertib is synergistic for pancreatic cancer, suggesting that this novel combination therapy has value in the treatment strategy of patients with pancreatic cancer.
Radiodermatitis is one of the commonest side effects of radiotherapy. They are usually assessed by semi‐quantitative clinical scores, which are not validated and may be subject to inter‐observer ...variability. A few previous studies suggested that high‐frequency ultrasonography (HF‐USG) is useful in the assessment of the acute phase of radiation dermatitis in breast cancer patients. (a) To monitor skin changes by HF‐USG during the course of radiotherapy due to head and neck cancers, and (b) to determine whether there is any connection between skin sonograms and the skin scoring criteria. This prospective, observational study includes patients diagnosed with head and neck cancers, treated with radiotherapy or concomitant chemoradiation. The final analysis includes six patients. In every patient, the HF‐USG as well as dermatological assessment (target lesion score—TLS and CACE v. 4.0) were performed 4×: before, in the middle, day after, and 3 months after radiotherapy. There were significant differences between non‐irradiated skin thickness and thickness of skin with clinically obvious radiodermatitis (TLS grade 1‐4; P < .0001), as well as between irradiated, unchanged skin thickness (TLS grade 0) and thickness of skin with clinically obvious radiodermatitis (TLS grade 1‐4; P = .0002). There was no significant difference between non‐irradiated and irradiated, unchanged skin thickness (TLS grade 0; P = .9318). In four patients, we demonstrated subepidermal low echogenic band (SLEB). HF‐USG can be useful tool to noninvasive and objective assessment of skin changes during radiotherapy.
Many intensive studies are devoted to identifying novel cancer diagnostics or therapy strategies that would boost cancer therapy efficacy and recovery rates. Importantly, polymorphisms in the genes ...coding for ABC family proteins were considered good candidates for cancer development risk or cancer drug resistance markers. For this reason, we decided to assess the contribution of ABCB1's most common variants (i.e., G2677T/A in exon 21/rs2032582 and C3435T in exon 26/rs1045642) to the cancer therapy response in breast cancer patients. A 10-year follow-up analysis of 157 breast cancer patients was performed. Clinical assessment, ABCB1 polymorphism status, estrogen/progesterone/human epidermal receptors status, and other characteristics were compared according to the follow-up status using the Chi-square statistic. For the analysis of overall survival curves in TCGA breast cancer patients, the Xena browser was used. We show that neither 2677 nor 3435 polymorphisms contributed to the survival of breast cancer patients. Interestingly, but not surprisingly, estrogen and progesterone receptors status were good prognostic factors and positively correlated with a disease-free survival for up to 10 years. To summarize,
polymorphisms status may be one of the numerous factors that affect cancer development. However, they may not be the critical ones when it comes to risk or recovery assessment. Consequently, they may not be treated as reliable prognostic or predictive markers in breast cancer patients' evaluation, which supports the previous findings and current knowledge.
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