ABSTRACT
We present a novel thermodynamic approach to the epigenomics of cancer metabolism. Here, any change in a cancer cell's membrane electric potential is completely irreversible, and as such, cells must consume metabolites to reverse the potential whenever required to maintain cell activity, a process driven by ion fluxes. Moreover, the link between cell proliferation and the membrane's electric potential is for the first time analytically proven using a thermodynamic approach, highlighting how its control is related to inflow and outflow of ions; consequently, a close interaction between environment and cell activity emerges. Lastly, we illustrate the concept by evaluating the Fe2+-flux in the presence of carcinogenesis-promoting mutations of the TET1/2/3 gene family.
Subject(s)
Neoplasms , Humans , Thermodynamics , Membrane Potentials , Cell Proliferation , Mixed Function Oxygenases , Proto-Oncogene ProteinsABSTRACT
In our recent studies, we have developed a thermodynamic biochemical model able to select the resonant frequency of an extremely low frequency electromagnetic field (ELF-EMF) specifically affecting different types of cancer, and we have demonstrated its effects in vitro. In this work, we investigate the cellular response to the ELF electromagnetic wave in three-dimensional (3D) culture models, which mimic the features of tumors in vivo. Cell membrane was modelled as a resistor-capacitor circuit and the specific thermal resonant frequency was calculated and tested on two-dimensional (2D) and three-dimensional (3D) cell cultures of human pancreatic cancer, glioblastoma and breast cancer. Cell proliferation and the transcription of respiratory chain and adenosine triphosphate synthase subunits, as well as uncoupling proteins, were assessed. For the first time, we demonstrate that an ELF-EMF hampers growth and potentiates both the coupled and uncoupled respiration of all analyzed models. Interestingly, the metabolic shift was evident even in the 3D aggregates, making this approach particularly valuable and promising for future application in vivo, in aggressive cancer tissues characterized by resistance to treatments.
Subject(s)
Electromagnetic Fields , Glioblastoma , Cell Proliferation , Electromagnetic Radiation , HumansABSTRACT
The fight against a multifaceted incurable disease such as cancer requires a multidisciplinary approach to overcome the multitude of molecular defects at its origin. Here, a new thermophysical biochemical approach has been suggested and associated with the use of electromagnetic fields to control the growth of cancer cells. In particular, thermodynamic analysis of the heat transfer is developed in correlation with cellular parameters such as the volume/area ratio. We propose that the electromagnetic wave, at the specific frequency calculated as the characteristic response time of any cell type to the external thermal perturbation, can affect resonant intracellular molecular oscillations. The biochemical model hypothesizes that microtubules are stabilized, and the impact is predicted on cell growth, migration and mitochondrial activity. Experimental validation of the theoretical results shows that the thermodynamic analysis allows the application of the specific electromagnetic field able to decrease cancer cell invasion and proliferation.
Subject(s)
Glaucoma, Open-Angle , Intraocular Pressure , Humans , Latin America , Risk Factors , White PeopleABSTRACT
Glaucoma is a multifactorial optic neuropathy characterized by the continuous loss of retinal ganglion cells, leading to progressive and irreversible visual impairment. In this minireview, we report the results of the most recent experimental studies concerning cells, molecular mechanisms, genes, and microbiome involved in neuroinflammation processes correlated to glaucoma neurodegeneration. The identification of cellular mechanisms and molecular pathways related to retinal ganglion cell death is the first step toward the discovery of new therapeutic strategies. Recent experimental studies identified the following possible targets: adenosine A2A receptor, sterile alpha and TIR motif containing 1 (neurofilament light chain), toll-like receptors (TLRs) 2 and 4, phosphodiesterase type 4 (PDE4), and FasL-Fas signaling (in particular ONL1204, a small peptide antagonist of Fas receptors), and therapies directed against them. The continuous progress in knowledge provides interesting data, although the total lack of human studies remains an important limitation. Further research is required to better define the role of neuroinflammation in the neurodegeneration processes that occur in glaucomatous disease and to discover neuroprotective treatments amenable to clinical trials. The hereinafter reviewed studies are reported and evaluated according to their translational relevance.
Subject(s)
Pre-Eclampsia , Blood Coagulation , Blood Platelets , Female , Humans , Platelet Activation , Platelet Function Tests , PregnancySubject(s)
Atherosclerosis , Peripheral Arterial Disease , Humans , Magnesium , Prevalence , Risk FactorsSubject(s)
Brain Ischemia , Helicobacter Infections , Helicobacter pylori , Stroke , Humans , PrevalenceSubject(s)
Helicobacter Infections , Helicobacter pylori , Anti-Bacterial Agents , Bismuth , Humans , Proton Pump InhibitorsSubject(s)
Pre-Eclampsia , Pregnancy Complications, Cardiovascular , Calcium , Dietary Supplements , Double-Blind Method , Female , Humans , PregnancyABSTRACT
The efficacy of the very low frequency electromagnetic field in cancer treatment remains elusive due to a lack of explanatory mechanisms for its effect. We developed a novel thermodynamic model that calculates for every cell type the frequency capable of inhibiting proliferation. When this frequency was applied to two human cancer cell lines, it reduced their growth while not affecting healthy cells. The effect was abolished by the inhibition of calcium fluxes. We found evidences of an enhanced respiratory activity due to the increased expression of the elements of the respiratory chain and oxidative phosphorylation, both at the mRNA and protein level. The respiratory burst potentiated the production of reactive oxygen species but was not associated to increased levels of ATP, leading to the conclusion that the energy was readily spent in the adaptive response to the electromagnetic field. Taken together, our data demonstrate that, regardless of individual molecular defects, it is possible to control cancer cells with a specific irradiation that imposes a mitochondrial metabolic switch, regulating calcium fluxes and deleterious to cancer growth. This approach lays the foundations for a personalized cancer medicine.
Subject(s)
Electromagnetic Fields , Neoplasms/radiotherapy , Cell Cycle , Cell Line, Tumor , Cell Proliferation/radiation effects , Cell Respiration , Epithelial Cells , Humans , Mitochondria/metabolism , Models, Biological , Oxidative Phosphorylation , Reactive Oxygen Species/metabolism , ThermodynamicsABSTRACT
The association of HCV-infection with B-lymphomas is supported by the regression of most indolent/low-grade lymphomas following anti-viral therapy. Studies on direct and indirect oncogenic mechanisms have elucidated the pathogenesis of HCV-associated B-lymphoma subtypes. These include B-lymphocyte proliferation and sustained clonal expansion by HCV-envelope protein stimulation of B-cell receptors, and prolonged HCV-infected B-cell growth by overexpression of an anti-apoptotic BCL-2 oncogene caused by the increased frequency of t(14;18) chromosomal translocations in follicular lymphomas. HCV has been implicated in lymphomagenesis by a "hit-and-run" mechanism, inducing enhanced mutation rate in immunoglobulins and anti-oncogenes favoring immune escape, due to permanent genetic damage by double-strand DNA-breaks. More direct oncogenic mechanisms have been identified in cytokines and chemokines in relation to NS3 and Core expression, particularly in diffuse large B-cell lymphoma. By reviewing genetic alterations and disrupted signaling pathways, we intend to highlight how mutually non-contrasting mechanisms cooperate with environmental factors toward progression of HCV-lymphoma.