Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respira... more Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the syn...
The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this con... more 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 charact...
An Innovative Approach to Understanding and Treating Cancer: Targeting pH, 2020
Abstract Migration and invasion play major roles in the process of metastasis. The driving of mig... more Abstract Migration and invasion play major roles in the process of metastasis. The driving of migration and invasion is the result of growth factors stimulating proton exchangers and channels, mainly NHE1, voltage gated sodium channels (VGSCs) and aquaporins (AQP), creating an acidic microenvironment, adequate for the activity of proteolytic enzymes. They increase intracellular alkalosis producing cell polarization and an intracellular pH gradient that goes from the rear part (lower pHi) to the advancing edge (higher pHi) of the cell. Correspondingly an extracellular gradient develops that is more acidic at the advancing edge. Migration takes place in the direction of the lowest pH. Aquaporins remove water from the rear part while incorporating it at the advancing front areas. Degradation of ECM occurring at invadopodia, small protrusions of plasmatic membrane and cytoplasm, by activation of acid-dependent proteolytic enzymes, allows invasion of surrounding tissues. Furthermore, the harsh acidic environment created by cancer cells induces death of normal cells around the tumor. Invadopodia are, therefore, the essential structures for invasion and eventual metastasis.
An Innovative Approach to Understanding and Treating Cancer: Targeting pH, 2020
Abstract We have not yet found the silver bullet that can kill cancer cells without seriously aff... more Abstract We have not yet found the silver bullet that can kill cancer cells without seriously affecting normal cells. However, there is one constant feature of cancer that is not usually present in normal tissues: an inverted pH gradient, where the intracellular pH becomes alkaline and the extracellular pH becomes acidic. This has been called the cancer pH-centered paradigm. This alteration, which has not yet received adequate consideration in cancer therapeutics—is a hallmark of all malignant cells and tissues. Research in the last 20 years has shown that modifying this abnormal pH has profound effects on the development of cancer and that pharmacological interventions are not only feasible but also have little effects on normal tissues. Strong evidence indicates that most of the pharmacological interventions that modify the pH gradient are compatible with standard treatments and enhance their results. This chapter will analyze the mechanisms involved in the pH inversion and its clinical implications.
Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success sto... more Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success story. The advances in surgery, chemotherapy and radiotherapy have not been sufficient at all. Indeed, the accumulated experience clearly indicates that new perspectives and non-main stream approaches are needed to better characterize the etiopathogenesis and treatment of this disease. This contribution deals with how the new pH-centric anticancer paradigm plays a fundamental role in reaching a more integral understanding of the etiology, pathogenesis, and treatment of this multifactorial disease. For the first time, the armamentarium available for the treatment of the different types and phases of BC is approached here from a Unitarian perspective-based upon the hydrogen ion dynamics of cancer. The wide-ranged pH-related molecular, biochemical and metabolic model is able to embrace most of the fields and subfields of breast cancer etiopathogenesis and treatment. This single and integrated ...
The treatment of cancer has been slowly but steadily progressing during the last fifty years. Som... more 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 therap...
Different research groups have recently described a proton [H(+)]-related mechanism underlying th... more Different research groups have recently described a proton [H(+)]-related mechanism underlying the initiation and progression of the neoplastic process 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 (pH(i) to pH(e)) as compared to normal tissue pH gradients. This basic specific abnormality of the relationship between the intracellular and the extracellular proton dynamics, a phenomenon that is increasingly considered to be one of the most differential hallmarks of cancer, has led to the formation of a unifying thermodynamic view of cancer research that embraces cancer fields from etiopathogenesis, cancer cell metabolism, multiple drug resistance (MDR), neovascularization and the metastatatic process t...
Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intrace... more 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...
A comprehensive examination of phenomena related to cancer is presented that is based on hydrogen... more A comprehensive examination of phenomena related to cancer is presented that is based on hydrogen ion dynamics, as viewed from the biological, biochemical, and biophysical perspective. A model is described that considers an array of cancer-associated events from oncogenesis to carcinogenesis from this perspective. The basic ideas are viewed from various aspects, ranging from the cellular level to the clinical situation. The novel types of therapeutic and prophylactic agents that result from applying these concepts are elucidated. Considerable insight into this modern approach is seen from some of the mechanisms that characterize the phenomenon of spontaneous regression of cancer.
Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respira... more Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the syn...
The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this con... more 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 charact...
An Innovative Approach to Understanding and Treating Cancer: Targeting pH, 2020
Abstract Migration and invasion play major roles in the process of metastasis. The driving of mig... more Abstract Migration and invasion play major roles in the process of metastasis. The driving of migration and invasion is the result of growth factors stimulating proton exchangers and channels, mainly NHE1, voltage gated sodium channels (VGSCs) and aquaporins (AQP), creating an acidic microenvironment, adequate for the activity of proteolytic enzymes. They increase intracellular alkalosis producing cell polarization and an intracellular pH gradient that goes from the rear part (lower pHi) to the advancing edge (higher pHi) of the cell. Correspondingly an extracellular gradient develops that is more acidic at the advancing edge. Migration takes place in the direction of the lowest pH. Aquaporins remove water from the rear part while incorporating it at the advancing front areas. Degradation of ECM occurring at invadopodia, small protrusions of plasmatic membrane and cytoplasm, by activation of acid-dependent proteolytic enzymes, allows invasion of surrounding tissues. Furthermore, the harsh acidic environment created by cancer cells induces death of normal cells around the tumor. Invadopodia are, therefore, the essential structures for invasion and eventual metastasis.
An Innovative Approach to Understanding and Treating Cancer: Targeting pH, 2020
Abstract We have not yet found the silver bullet that can kill cancer cells without seriously aff... more Abstract We have not yet found the silver bullet that can kill cancer cells without seriously affecting normal cells. However, there is one constant feature of cancer that is not usually present in normal tissues: an inverted pH gradient, where the intracellular pH becomes alkaline and the extracellular pH becomes acidic. This has been called the cancer pH-centered paradigm. This alteration, which has not yet received adequate consideration in cancer therapeutics—is a hallmark of all malignant cells and tissues. Research in the last 20 years has shown that modifying this abnormal pH has profound effects on the development of cancer and that pharmacological interventions are not only feasible but also have little effects on normal tissues. Strong evidence indicates that most of the pharmacological interventions that modify the pH gradient are compatible with standard treatments and enhance their results. This chapter will analyze the mechanisms involved in the pH inversion and its clinical implications.
Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success sto... more Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success story. The advances in surgery, chemotherapy and radiotherapy have not been sufficient at all. Indeed, the accumulated experience clearly indicates that new perspectives and non-main stream approaches are needed to better characterize the etiopathogenesis and treatment of this disease. This contribution deals with how the new pH-centric anticancer paradigm plays a fundamental role in reaching a more integral understanding of the etiology, pathogenesis, and treatment of this multifactorial disease. For the first time, the armamentarium available for the treatment of the different types and phases of BC is approached here from a Unitarian perspective-based upon the hydrogen ion dynamics of cancer. The wide-ranged pH-related molecular, biochemical and metabolic model is able to embrace most of the fields and subfields of breast cancer etiopathogenesis and treatment. This single and integrated ...
The treatment of cancer has been slowly but steadily progressing during the last fifty years. Som... more 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 therap...
Different research groups have recently described a proton [H(+)]-related mechanism underlying th... more Different research groups have recently described a proton [H(+)]-related mechanism underlying the initiation and progression of the neoplastic process 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 (pH(i) to pH(e)) as compared to normal tissue pH gradients. This basic specific abnormality of the relationship between the intracellular and the extracellular proton dynamics, a phenomenon that is increasingly considered to be one of the most differential hallmarks of cancer, has led to the formation of a unifying thermodynamic view of cancer research that embraces cancer fields from etiopathogenesis, cancer cell metabolism, multiple drug resistance (MDR), neovascularization and the metastatatic process t...
Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intrace... more 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...
A comprehensive examination of phenomena related to cancer is presented that is based on hydrogen... more A comprehensive examination of phenomena related to cancer is presented that is based on hydrogen ion dynamics, as viewed from the biological, biochemical, and biophysical perspective. A model is described that considers an array of cancer-associated events from oncogenesis to carcinogenesis from this perspective. The basic ideas are viewed from various aspects, ranging from the cellular level to the clinical situation. The novel types of therapeutic and prophylactic agents that result from applying these concepts are elucidated. Considerable insight into this modern approach is seen from some of the mechanisms that characterize the phenomenon of spontaneous regression of cancer.
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Papers by Salvador Harguindey