Hydrogen Ion Dynamics as the Fundamental Link between Neurodegenerative Diseases and Cancer: Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis on Multiple Sclerosis.

The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally assessed for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study (molecular, biochemical, metabolic, and clinical), the intimate nature of both processes appears to consist of opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranging original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows us to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) is an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Furthermore, within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth. Finally, and for the first time, a new and integrated model of treatment for MS can now be advanced.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era.

A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H+) dynamics of cancer, allows for the understanding and integration of the many dualisms, confusions, and paradoxes of the disease. The new H+-related, wide-ranging model can embrace, from a unique perspective, the many aspects of the disease and, at the same time, therapeutically interfere with most, if not all, of the hallmarks of cancer known to date. The pH-related armamentarium available for the treatment of BC reviewed here may be beneficial for all types and stages of the disease. In this vein, we have attempted a megasynthesis of traditional and new knowledge in the different areas of breast cancer research and treatment based upon the wide-ranging approach afforded by the hydrogen ion dynamics of cancer. The concerted utilization of the pH-related drugs that are available nowadays for the treatment of breast cancer is advanced.

Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies.

The treatment of cancer has been slowly but steadily progressing during the last fifty years. Some tumors with a high mortality in the past are curable nowadays. However, there is one striking exception: glioblastoma multiforme. No real breakthrough has been hitherto achieved with this tumor with ominous prognosis and very short survival. Glioblastomas, being highly glycolytic malignancies are strongly pH-dependent and driven by the sodium hydrogen exchanger 1 (NHE1) and other proton (H+) transporters. Therefore, this is one of those pathologies where the lessons recently learnt from the new pH-centered anticancer paradigm may soon bring a promising change to treatment. This contribution will discuss how the pH-centric molecular, biochemical and metabolic perspective may introduce some urgently needed and integral novel treatments. Such a prospective therapeutic approach for malignant brain tumors is developed here, either to be used alone or in combination with more standard therapies.

Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases.

During the last few years, the understanding of the dysregulated hydrogen ion dynamics and reversed proton gradient of cancer cells has resulted in a new and integral pH-centric paradigm in oncology, a translational model embracing from cancer etiopathogenesis to treatment. The abnormalities of intracellular alkalinization along with extracellular acidification of all types of solid tumors and leukemic cells have never been described in any other disease and now appear to be a specific hallmark of malignancy. As a consequence of this intracellular acid-base homeostatic failure, the attempt to induce cellular acidification using proton transport inhibitors and other intracellular acidifiers of different origins is becoming a new therapeutic concept and selective target of cancer treatment, both as a metabolic mediator of apoptosis and in the overcoming of multiple drug resistance (MDR). Importantly, there is increasing data showing that different ion channels contribute to mediate significant aspects of cancer pH regulation and etiopathogenesis. Finally, we discuss the extension of this new pH-centric oncological paradigm into the opposite metabolic and homeostatic acid-base situation found in human neurodegenerative diseases (HNDDs), which opens novel concepts in the prevention and treatment of HNDDs through the utilization of a cohort of neural and non-neural derived hormones and human growth factors.

Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question.

Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intracellular alkaline pH (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then proposea new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced.

Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs--an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research.

In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and treatment. A proton [H+]-related mechanism underlying the initiation and progression of the neoplastic process has been recently described by different research groups as a new paradigm in which all cancer cells and tissues, regardless of their origin and genetic background, have a pivotal energetic and homeostatic disturbance of their metabolism that is completely different from all normal tissues: an aberrant regulation of hydrogen ion dynamics leading to a reversal of the pH gradient in cancer cells and tissues (↑pHi/↓pHe, or "proton reversal"). Tumor cells survive their hostile microenvironment due to membrane-bound proton pumps and transporters, and their main defensive strategy is to never allow internal acidification because that could lead to their death through apoptosis. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). An elevated NHE1 activity can be correlated with both an increase in cell pH and a decrease in the extracellular pH of tumors, and such proton reversal is associated with the origin, local growth, activation and further progression of the metastatic process. Consequently, NHE1 pharmaceutical inhibition by new and potent NHE1 inhibitors represents a potential and highly selective target in anticancer therapy. Cariporide, being one of the better studied specific and powerful NHE1 inhibitors, has proven to be well tolerated by humans in the cardiological context, however some side-effects, mainly related to drug accumulation and cerebrovascular complications were reported. Thus, cariporide could become a new, slightly toxic and effective anticancer agent in different human malignancies.