Review
The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin—one single nature

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Abstract

Looked at from the genetic point-of-view cancer represents a daunting and, frankly, confusing multiplicity of diseases (at least 100) that require an equally large variety of therapeutic strategies and substances designed to treat the particular tumor. However, when analyzed phenotypically cancer is a relatively uniform disease of very conserved ‘hallmark’ behaviors across the entire spectrum of tissue and genetic differences [D. Hanahan, R.A. Weinberg, Hallmarks of cancer, Cell 100 (2000) 57–70]. This suggests that cancers do, indeed, share common biochemical and physiological characteristics that are independent of the varied genetic backgrounds, and that there may be a common mechanism underlying both the neoplastic transformation/progression side and the antineoplastic/therapy side of oncology. The challenge of modern oncology is to integrate all the diverse experimental data to create a physiological/metabolic/energetic paradigm that can unite our thinking in order to understand how both neoplastic progression and therapies function. This reductionist view gives the hope that, as in chemistry and physics, it will possible to identify common underlying driving forces that define a tumor and will permit, for the first time, the actual calculated manipulation of their state. That is, a rational therapeutic design. In the present review, we present evidence, obtained from a great number of studies, for a fundamental, underlying mechanism involved in the initiation and evolution of the neoplastic process. There is an ever growing body of evidence that all the important neoplastic phenotypes are driven by an alkalization of the transformed cell, a process which seems specific for transformed cells since the same alkalinization has no effect in cells that have not been transformed. Seen in that light, different fields of cancer research, from etiopathogenesis, cancer cell metabolism and neovascularization, to multiple drug resistance (MDR), selective apoptosis, modern cancer chemotherapy and the spontaneous regression of cancer (SRC) all appear to have in common a pivotal characteristic, the aberrant regulation of hydrogen ion dynamics [S. Harguindey, J.L. Pedraz, R. García Cañero, J. Pérez de Diego, E.J. Cragoe Jr., Hydrogen ion-dependent oncogenesis and parallel new avenues to cancer prevention and treatment using a H+-mediated unifying approach: pH-related and pH-unrelated mechanisms, Crit. Rev. Oncog. 6 (1) (1995) 1–33]. Cancer cells have an acid–base disturbance that is completely different than observed in normal tissues and that increases in correspondence with increasing neoplastic state: an interstitial acid microenvironment linked to an intracellular alkalosis.

Introduction

At one end of a H+-concentration spectrum (high pH or alkaline limiting zone), the induction and/or maintenance of an abnormally high intracellular alkalinization has been repeatedly implicated as playing an essential, direct and pivotal role both in neoplastic transformation as well as in the active maintenance and progression of the neoplastic process [2], [3], [4], [5], [6] (Fig. 1). These different sets of data have recently led various authors to suggest that one of the hallmark characteristics of cancer cells of many different tissues and genetic origins may be the systematic loss of the rigid control of pHi in both the acute and in the chronic situation [2], [4], [7]. Independent of genetic variability, cellular pathological alkalosis, together with an abnormally high glycolytic metabolism that has been recognized since the time of Otto Warburg, are two of the principal factors characterizing cancer cells and malignant tumors in general [2], [4], [8], [9], [10], [11], [12], [13]. Indeed, the high glycolytic rate of tumors, which can be correlated with the degree of malignancy in many tumor types, is taken advantage of in some of the most modern diagnostic techniques used to detect the presence of malignant tumors and their metastases: positron emission tomography (PET) [10], [14], [15], [16]. Such a systemic abnormality of cellular acid–base homeostasis also plays a key role in the transduction of intracellular signals of a wide array of growth factors, a feature often, but not always, mediated by stimulation of the plasma membrane Na+/H+ antiporter isoform 1, also known as the Na+/H+ exchanger isoform 1 (NHE1). This electroneutral transporter expels hydrogen ions out of the cell while interchanging them for Na+ and thereby increasing intracellular Na+ and alkalinizing intracellular pH (pHi). In normal cells, the NHE1 is quiescent at the steady state resting pHi. and is activated only upon cytosolic acidification [6], [7], [17], [18]. In transformed and cancer cells, the NHE1 is hyperactive even at resting pH and the resulting change in cellular alkalinity has been shown to be directly related in most cases to the permanent and uncontrolled proliferation characteristic of neoplastic cells [4], [19], [20], [21], [22]. Recently, compelling evidence has come to light indicating that the activity of the NHE1 is also a critical factor in the activation of proliferation, motility and invasion of cancer cells derived from various tissues [4], [22], [23], [24], [25], [26], [27], [28].

On the other side of the coin, there currently appears to be a dead-lock in the present state of cancer chemotherapy [29]. This seems to be related to the fact that most of the antitumor agents used in the clinical situation are based upon the old “anti DNA” paradigm which during the last 60 years has attempted to induce an antitumor effect by targeting DNA synthesis or cell division and proliferation. It has been recently proposed that the modest progress achieved and the lack of selectivity of current antitumor agents suggests that the “anti DNA” framework is either wrong or at least too simplistic and conceptually poor from the very beginning for such a complex disease [29], [30]. Some of these authors have proposed that the limitations of the present-day approaches can be responsible for the fact that some therapies can even exacerbate the original malignant phenotype, induce escape from apoptosis and negatively affect the progression of the disease [30], [31], [32]. Recently, a new therapeutic perspective is developing which targets cell membrane or signal transduction proteins instead of DNA synthesis. This change is taking place after an increasing bulk of evidence has led researchers to try to trigger mechanisms to induce selective cancer cell death by apoptosis. This relatively new approach is changing the old and aggressive concept of going for “a direct kill of cancer cells” for a more benevolent “help or induce to die” concept. In an attempt to bring together both paradigms, the failure of tumor cells to die following chemotherapeutic treatment appears to be mostly dependent on their resistance to engaging in the apoptotic process [29].

In summary, the purpose of this review is an attempt to analyze and then synthesize the seminal and emerging data in these areas in order to: (i) to interpret the neoplastic process from the point of view of the critical mechanistic level in order to draw basic research and clinical therapeutics nearer to each other; (ii) unite both therapeutic paradigms into a single and more comprehensive one; and (iii) open new directions in cancer prevention and treatment.

Section snippets

Intracellular pH (pHi) and extracellular pH (pHe) in tumors: interrelationships and physiopathological significance

From the beginning of biochemical cancer research decades ago and until today, the relationships between intracellular pH (pHi) and extracellular (pHe) within a tumor have been a highly controversial issue and an unending source of confusion [33], [34]. For many decades, tumor cells were thought to be have an acidic pHi [16], [33]. However, in the last few years, it has been repeatedly shown that cancer cells show a strong tendency towards an alkaline deviation of the entire acid–base

The other side of the coin: regression and treatment

At the other end of an H+-concentration spectrum (low pH, or acid limiting zone), it becomes necessary to analyze which factors and/or mediating mechanisms may lead the entire homeostasis of cell physiology towards a “therapeutic” acidification in the cancer setting. A great deal of experimental evidence coming from modern biochemistry and molecular biology backs up this etiological approach to treatment whose importance is rapidly growing in the context of cancer treatment and innovative

Implications and conclusions. New strategies designed to induce selective apoptosis and overcome resistance to cytotoxic agents

From infectious to neoplastic disease, an etiological and/or unifying approach to the treatment of any disease process should always be sought after (the root approach). In the case of cancer research, this perspective was aimed at uniting under the same view such diverse aspects of oncology ranging from “etiology” to therapeutics. On both sides of this continuum, the highly significant role first of a high pHi in the origin, development and maintenance of the neoplastic state and, secondly,

Acknowledgements

This work was supported by grants of the Castresana Foundation, Vitoria, Spain, PSO CNR-MIUR Grant CU03.00304, FIRB Grant RBAU01B3A3-001 and the Center of Excellence in Biomedical and Agrarian Genomics (CEGBA) of the University of Bari, Italy. We thank Dr. Miriam L. Wahl and Dr. Ignacio Gil Bazo for bibliographic assistance. Moreover, the authors apologize to all investigators who have significantly contributed to the different fields of cancer research studied in this contribution, but whose

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