An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs) and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS)

Harguindey, Salvador; Orive, Gorka; Cacabelos, Ramón; Hevia, Enrique Meléndez; Otazu, R. Díaz de; Arranz, Jose Luis; Anitua, Eduardo

doi:10.2147/ndt.s3800

Cited by 11 publications

(41 citation statements)

References 149 publications

(270 reference statements)

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“…Regarding NHE-related malignant angiogenesis, the activity of a significant number of proangiogenic factors and oncogenes has been shown to positively affect NHE1 expression while, on the contrary, a wide array of anti-angiogenic drugs inhibit NHE1 [ 272 , 273 ]. Conversely, decreasing NHE1 expression or inhibiting NHE1 activity leads to acidification of the intracellular space and so to the inhibition of glycolysis, thus to tumour cell growth arrest and, finally, to selective apoptosis [ 234 , 267 , 274 , 275 ]. Consequently, the new, potent and highly selective NHE1 inhibitors - mainly Cariporide, Phx-3 and Compound 9t - appear predestined to be taken advantage of as a new and highly selective therapeutic “magic bullets” in probably most types of human cancer [ 51 , 263 , 276 - 278 ].…”

Section: Anticancer and Antimetastatic Potential Of The New And Potenmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Anticancer and Antimetastatic Potential Of The New And Potenmentioning

confidence: 99%

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

et al. 2014

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“…Ion channels (ICs) are highly important membrane-bound additional factors in the etiopathogenesis of both cancer and human neurodegenerative diseases (HNDDs), pathologies that, from an acid–base point of view, dwell at both ends of a metabolic, biochemical and molecular spectrum [ 4 , 5 , 6 ]. In the cancer context, the most selective VGSC isoform is the NaV1.5-Na + channel, which is synergistically associated with NHE1, both being overexpressed in BC and other tumors.…”

Section: Breast Cancer Ph-related Etiology and Pathogenesis The mentioning

confidence: 99%

“…The model described here considers all aspects of malignancy from one single and integral perspective in order to embrace a wide array of apparently unrelated factors involved in the etiopathogenesis of BC [ 4 ]. This approach, based upon the cancer-selective and deregulated proton (H + ) dynamics in cancer, allows us to reach a new and deeper understanding of the intimate energetics of the acid–base dynamic nature of any malignant process, as well as of human neurodegenerative diseases (HNDDs), the latter as a beneficial side effect of the H + -related outreaching paradigm [ 4 , 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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

Harguindey¹,

Alfarouk

Orozco³

et al. 2020

IJMS

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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.

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“…This “chain-reaction” of deep-seated and dynamically disregulated H + energetics creates a “perfect storm for cancer progression” [ 2 ]. Finally, to our knowledge the pathological alkaline pH i of tumor cells and tissues have never been described in any other type of cell or disease other than malignancy [ 29 , 30 ]. This adds further weight to the paradigm concerning the specificity and selectivity of these H + -mediated, deep-seated energetic abnormalities regarding the advantageous thermodynamics of the malignant process.…”

Section: Rationalementioning

confidence: 99%

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

Harguindey¹,

Arranz²,

Orozco³

et al. 2013

Journal of Translational Medicine

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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.

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An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs) and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS)

Cited by 11 publications

References 149 publications

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

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

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

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

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