311 results found
Fraser SP, Tesi A, Bonito B, et al., 2021, Potassium Channel Blockage and Invasiveness of Strongly Metastatic Prostate and Breast Cancer Cells, BIOELECTRICITY, Vol: 3, Pages: 215-220, ISSN: 2576-3105
Fraser SP, Onkal R, Theys M, et al., 2021, Neonatal NaV 1.5: Pharmacological distinctiveness of a cancer-related voltage-gated sodium channel splice variant., Br J Pharmacol
BACKGROUND AND PURPOSE: Voltage-gated sodium (NaV ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of NaV 1.5 (nNaV 1.5) which has several amino acid substitutions in the domain I voltage-sensor compared to its adult counterpart (aNaV 1.5). This study aimed to determine whether nNaV 1.5 could be distinguished pharmacologically from aNaV 1.5. EXPERIMENTAL APPROACH: Cells expressing either nNaV 1.5 or aNaV 1.5 were exposed to small-molecule inhibitors, an antibody or natural toxins, and changes in electrophysiological parameters were measured. Stable expression in EBNA cells and transient expression in Xenopus laevis oocytes were used. Currents were recorded by whole-cell patch clamp and two-electrode voltage-clamp, respectively. KEY RESULTS: Several clinically-used blockers of Nav channels (lidocaine, procaine, phenytoin, mexiletine, ranolazine and riluzole) could not distinguish between nNaV 1.5 or aNaV 1.5. On the other hand, two tarantula toxins (HaTx and ProTx-II) and a polyclonal antibody (NESOpAb) preferentially inhibited currents elicited by either nNaV 1.5 or aNaV 1.5 by binding to the spliced region of the channel. Furthermore, the amino acid residue at position 211 (aspartate in aNaV 1.5/lysine in nNaV 1.5), i.e. the charge reversal in the spliced region of the channel, played a key role in the selectivity especially in the antibody binding. CONCLUSION AND IMPLICATIONS: We conclude that the cancer-related nNaV 1.5 channel can be distinguished pharmacologically from its nearest neighbour, aNaV 1.5. Thus, it may be possible to design small molecules as anti-metastatic drugs for non-toxic therapy of nNaV 1.5-expressing carcinomas.
Djamgoz MBA, Levin M, 2021, Bioelectricity Is the Bridge Where Cancer Meets Neuroscience, BIOELECTRICITY, Vol: 3, Pages: 159-160, ISSN: 2576-3105
Lastraioli E, Fraser SP, Guzel RM, et al., 2021, Neonatal Nav1.5 protein expression in human colorectal cancer: immunohistochemical characterization and clinical evaluation, Cancers, Vol: 13, Pages: 1-14, ISSN: 2072-6694
Voltage-gated Na+ channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker (‘companion diagnostic’) useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments.
Djamgoz MBA, Jentzsch V, 2021, Integrative management of pancreatic cancer (PDAC): emerging complementary agents and modalities, Nutrition and Cancer: an international journal, ISSN: 0163-5581
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. The standard first-line treatment for PDAC is gemcitabine chemotherapy which, unfortunately, offers only limited chance of a lasting cure. This review further evaluates the hypothesis that the effectiveness of gemcitabine can be improved by combining it with evidence-based complementary measures. Previously, supported by clinical trial data, we suggested that a number of dietary factors and nutraceuticals can be integrated with gemcitabine therapy. Here, we evaluate a further 10 agents for which no clinical trials have (yet) been carried out but there are promising data from in vivo and/or in vitro studies including experiments involving combined treatments with gemcitabine. Two groups of complementary agents are considered: Dietary factors (resveratrol, epigallocatechin gallate, vitamin B9, capsaicin, quercetin and sulforaphane) and nutraceutical agents (artemisinin, garcinol, thymoquinone and emodin). In addition, we identified seven promising agents for which there is currently only basic (mostly in vitro) data. Finally, as a special case of combination therapy, we highlighted synergistic drug combinations involving gemcitabine with “repurposed” aspirin or metformin. We conclude overall that integrated management of PDAC currently is likely to produce the best outcome for patients and for this a wide range of complementary measures is available.
Hutchings C, Phillips JA, Djamgoz MBA, 2020, Nerve input to tumours: Pathophysiological consequences of a dynamic relationship, BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, Vol: 1874, ISSN: 0304-419X
Jentzsch V, Davis JAA, Djamgoz MBA, 2020, Pancreatic Cancer (PDAC): introduction of evidence-based complementary measures into integrative clinical management, Cancers, Vol: 12, Pages: 1-62, ISSN: 2072-6694
The most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which comprises some 85% of all cases. Currently, this is the fourth highest cause of cancer mortality worldwide and its incidence is rising steeply. Commonly applied clinical therapies offer limited chance of a lasting cure and the five-year survival rate is one of the lowest of the commonly occurring cancers. This review cultivates the hypothesis that the best management of PDAC would be possible by integrating ‘western’ clinical medicine with evidence-based complementary measures. Protecting the liver, where PDAC frequently first spreads, is also given some consideration. Overall, the complementary measures are divided into three groups: dietary factors, nutraceutical agents and lifestyle. In turn, dietary factors are considered as general conditioners, multi-factorial foodstuffs and specific compounds. The general conditioners are alkalinity, low-glycemic index and low-cholesterol. The multi-factorial foodstuffs comprise red meat, fish, fruit/vegetables, dairy, honey and coffee. The available evidence for the beneficial effects of the specific dietary and nutraceutical agents was considered at four levels (in order of prominence): clinical trials, meta-analyses, in vivo tests and in vitro studies. Thus, 9 specific agents were identified (6 dietary and 3 nutraceutical) as acceptable for integration with gemcitabine chemotherapy, the first-line treatment for pancreatic cancer. The specific dietary agents were the following: Vitamins A, C, D and E, genistein and curcumin. As nutraceutical compounds, propolis, triptolide and cannabidiol were accepted. The 9 complementary agents were sub-grouped into two with reference to the main ‘hallmarks of cancer’. Lifestyle factors covered obesity, diabetes, smoking, alcohol and exercise. An integrative treatment regimen was devised for the management of PDAC patients. This involved combining first-line gemcitabine chem
Schofield Z, Meloni GN, Tran P, et al., 2020, Correction to ‘Bioelectrical understanding and engineering of cell biology’, Journal of the Royal Society Interface, Vol: 17, Pages: 1-1, ISSN: 1742-5662
Rizaner N, Uzun S, Fraser SP, et al., 2020, Riluzole: Anti-invasive effects on rat prostate cancer cells under normoxic and hypoxic conditions, BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, Vol: 127, Pages: 254-264, ISSN: 1742-7835
Schofield Z, Meloni GN, Tran P, et al., 2020, Bioelectrical understanding and engineering of cell biology, Journal of the Royal Society Interface, Vol: 17, Pages: 1-8, ISSN: 1742-5662
The last five decades of molecular and systems biology research have provided unprecedented insights into the molecular and genetic basis of many cellular processes. Despite these insights, however, it is arguable that there is still only limited predictive understanding of cell behaviours. In particular, the basis of heterogeneity in single-cell behaviour and the initiation of many different metabolic, transcriptional or mechanical responses to environmental stimuli remain largely unexplained. To go beyond the status quo, the understanding of cell behaviours emerging from molecular genetics must be complemented with physical and physiological ones, focusing on the intracellular and extracellular conditions within and around cells. Here, we argue that such a combination of genetics, physics and physiology can be grounded on a bioelectrical conceptualization of cells. We motivate the reasoning behind such a proposal and describe examples where a bioelectrical view has been shown to, or can, provide predictive biological understanding. In addition, we discuss how this view opens up novel ways to control cell behaviours by electrical and electrochemical means, setting the stage for the emergence of bioelectrical engineering.
Ribeiro M, Elghajiji A, Fraser SP, et al., 2020, Human breast cancer cells demonstrate electrical excitability, Frontiers in Neuroscience, Vol: 14, Pages: 1-10, ISSN: 1662-453X
Breast cancer is one of the most prevalent types of cancers worldwide and yet, its pathophysiology is poorly understood. Single-cell electrophysiological studies have provided evidence that membrane depolarization is implicated in the proliferation and metastasis of breast cancer. However, metastatic breast cancer cells are highly dynamic microscopic systems with complexities beyond a single-cell level. There is an urgent need for electrophysiological studies and technologies capable of decoding the intercellular signaling pathways and networks that control proliferation and metastasis, particularly at a population level. Hence, we present for the first time non-invasive in vitro electrical recordings of strongly metastatic MDA-MB-231 and weakly/non-metastatic MCF-7 breast cancer cell lines. To accomplish this, we fabricated an ultra-low noise sensor that exploits large-area electrodes, of 2 mm2, which maximizes the double-layer capacitance and concomitant detection sensitivity. We show that the current recorded after adherence of the cells is dominated by the opening of voltage-gated sodium channels (VGSCs), confirmed by application of the highly specific inhibitor, tetrodotoxin (TTX). The electrical activity of MDA-MB-231 cells surpasses that of the MCF-7 cells, suggesting a link between the cells’ bioelectricity and invasiveness. We also recorded an activity pattern with characteristics similar to that of Random Telegraph Signal (RTS) noise. RTS patterns were less frequent than the asynchronous VGSC signals. The RTS noise power spectral density showed a Lorentzian shape, which revealed the presence of a low-frequency signal across MDA-MB-231 cell populations with propagation speeds of the same order as those reported for intercellular Ca2+ waves. Our recording platform paves the way for real-time investigations of the bioelectricity of cancer cells, their ionic/pharmacological properties and relationship to metastatic potential.
Bugan I, Kucuk S, Karagoz Z, et al., 2019, Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate, PROSTATE CANCER AND PROSTATIC DISEASES, Vol: 22, Pages: 569-579, ISSN: 1365-7852
Lee A, Fraser SP, Djamgoz MBA, 2019, Propranolol inhibits neonatal Nav1.5 activity and invasiveness of MDA-MB-231 breast cancer cells: Effects of combination with ranolazine, JOURNAL OF CELLULAR PHYSIOLOGY, Vol: 234, Pages: 23066-23081, ISSN: 0021-9541
Djamgoz MBA, Fraser SP, Brackenbury WJ, 2019, In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis, CANCERS, Vol: 11
Farooqi AA, de la Roche M, Djamgoz MBA, et al., 2019, Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights, SEMINARS IN CANCER BIOLOGY, Vol: 58, Pages: 65-79, ISSN: 1044-579X
Guzel RM, Ogmen K, Ilieva KM, et al., 2019, Colorectal cancer invasiveness in vitro: Predominant contribution of neonatal Nav1.5 under normoxia and hypoxia, JOURNAL OF CELLULAR PHYSIOLOGY, Vol: 234, Pages: 6582-6593, ISSN: 0021-9541
Rizaner N, Onkal R, Fraser SP, et al., 2018, Involvement of Intracellular Ca2+Stores in Spontaneous Ca2+Oscillations in a Human Strongly Metastatic Prostate Cancer Cell, Publisher: WILEY, Pages: 52-52, ISSN: 1748-1708
Vysokov NV, Silva J-P, Lelianova VG, et al., 2018, Proteolytically released Lasso/teneurin-2 induces axonal attraction by interacting with latrophilin-1 on axonal growth cones, ELIFE, Vol: 7, ISSN: 2050-084X
Marshall HT, Djamgoz MBA, 2018, Immuno-Oncology: Emerging Targets and Combination Therapies, FRONTIERS IN ONCOLOGY, Vol: 8, ISSN: 2234-943X
Keles D, Sipahi M, Djamgoz MB, et al., 2018, Tetracaine suppress metastatic cell behaviors through regulating matrix metalloproteinase-2/-9 and TIMP-2 levels in metastatic breast cancer cells, Publisher: WILEY, Pages: 334-334, ISSN: 2211-5463
Sipahi M, Keles D, Djamgoz MB, et al., 2018, siRNA-directed inhibition of SCN5A increases matrix metalloproteinase-9 expression and activity in MDA-MB-231 metastatic breast cancer cells, Publisher: WILEY, Pages: 334-334, ISSN: 2211-5463
Cort A, Ozben T, Djamgoz MBA, 2018, Oxidative stress and voltage-gated sodium channel activity in human breast cancer cells, Publisher: WILEY, Pages: 359-360, ISSN: 2211-5463
Pchelintseva E, Djamgoz MBA, 2018, Mesenchymal stem cell differentiation: Control by calcium-activated potassium channels, JOURNAL OF CELLULAR PHYSIOLOGY, Vol: 233, Pages: 3755-3768, ISSN: 0021-9541
Lee A, Djamgoz MBA, 2018, Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies, CANCER TREATMENT REVIEWS, Vol: 62, Pages: 110-122, ISSN: 0305-7372
Djamgoz MBA, Akun E, Arslan B, et al., 2017, Cancer in North Cyprus: 1. Current Status, An Overview, CYPRUS JOURNAL OF MEDICAL SCIENCES, Vol: 2, Pages: 9-12, ISSN: 2149-7893
Djamgoz MBA, Akun E, Arslan B, et al., 2017, Cancer in North Cyprus: 2. Biomedical Research Activities, CYPRUS JOURNAL OF MEDICAL SCIENCES, Vol: 2, Pages: 13-18, ISSN: 2149-7893
Yamaci RF, Fraser SP, Battaloglu E, et al., 2017, Neonatal Nav1.5 protein expression in normal adult human tissues and breast cancer, PATHOLOGY RESEARCH AND PRACTICE, Vol: 213, Pages: 900-907, ISSN: 0344-0338
Arslan B, Djamgoz MBA, Akün E, 2016, ARSENIC: A Review on Exposure Pathways, Accumulation, Mobility and Transmission into the Human Food Chain., Rev Environ Contam Toxicol, Vol: 243, Pages: 27-51, ISSN: 0179-5953
This review deals with exposure pathways of arsenic (As), as well as its transfer and uptake processes from its source to the human body. It is proven fact that uptake of inorganic As for a long period can lead to chronic As poisoning and a variety of adverse health effects such as skin, lung and bladder cancer, in addition to cardiovascular diseases, diabetes and gastrointestinal symptoms. As exposure occurs primarily from consumption of potable water containing high amounts of inorganic As and also from consumption of crops cultivated in As contaminated agricultural fields-either naturally or anthropogenically through contaminated air or pesticides-or irrigated with As containing water. In this review, light is shed on the transfer mechanism of As through the food chain and the parameters that enhance mobility of As in the environment. Amounts of As accumulation in plants and the transfer mechanisms are also quite different. These differences in As accumulation, such as in leaves, stems, fruits and roots, are discussed in detail. Moreover, presence of As in some vegetables consumed is given by investigating recent research articles that deal with As concentrations, especially in edible parts. Some comparative data are also presented, concerning the level of concentration of As in rice during washing, cooking and processing stages.
Bonito B, Sauter DRP, Schwab A, et al., 2016, K(Ca)3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 468, Pages: 1865-1875, ISSN: 0031-6768
Rizaner N, Onkal R, Fraser SP, et al., 2016, Intracellular calcium oscillations in strongly metastatic human breast and prostate cancer cells: control by voltage-gated sodium channel activity., European Biophysics Journal, Vol: 45, Pages: 735-748, ISSN: 0175-7571
The possible association of intracellular Ca(2+) with metastasis in human cancer cells is poorly understood. We have studied Ca(2+) signaling in human prostate and breast cancer cell lines of strongly versus weakly metastatic potential in a comparative approach. Intracellular free Ca(2+) was measured using a membrane-permeant fluorescent Ca(2+)-indicator dye (Fluo-4 AM) and confocal microscopy. Spontaneous Ca(2+) oscillations were observed in a proportion of strongly metastatic human prostate and breast cancer cells (PC-3M and MDA-MB-231, respectively). In contrast, no such oscillations were observed in weakly/non metastatic LNCaP and MCF-7 cells, although a rise in the resting Ca(2+) level could be induced by applying a high-K(+) solution. Various parameters of the oscillations depended on extracellular Ca(2+) and voltage-gated Na(+) channel activity. Treatment with either tetrodotoxin (a general blocker of voltage-gated Na(+) channels) or ranolazine (a blocker of the persistent component of the channel current) suppressed the Ca(2+) oscillations. It is concluded that the functional voltage-gated Na(+) channel expression in strongly metastatic cancer cells makes a significant contribution to generation of oscillatory intracellular Ca(2+) activity. Possible mechanisms and consequences of the Ca(2+) oscillations are discussed.
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