Manipulating Cellular Acidification as
a New Approach to Cancer Treatment
Project Authors: Salvador Harguindey, MD, PhD
Director, Institute for Clinical Biology and Metabolism, Vitoria, Spain
& Jesús Devesa, MD, PhD
Professor of Physiology and Endocrinology, University of Santiago de Compostela, Spain
Scientific Director of the Medical Center Foltra
It is well accepted by now that in order to survive and develop, tumors require large amount of glucose. A good amount of this glucose is intensively processed by tumors via the fermentation process, to generate energy. During this process, as a side effect, tumors produce protons (hydrogen ions) that need to be exported outside the cell. This is because otherwise protons would acidify the cell, and reduce the internal pH to a level that would damage and possible kill the cancer cells.
Therefore, in the same way as the automobile requires an exhaust pipe to eliminate the smoke produced while the car is running, cancer cells amplify the proton transporters and proton pumps) on the cell membrane, increasing their capability to eliminate the acidity induced by protons.
This is how, proton pumps and transporters help cancer cells to maintain a high (alkaline) internal pH (pHi) by exporting protons to the tumor microenvironment. As a consequence, the space surrounding the tumors will be acidic (low pHe), which will further help tumors to survive, grow and metastasize.
During recent years, an increasing number of scientific data has emphasized the growing importance of proton dynamics in modern cancer research, from etiopathogenesis and treatment point of view. As a result, along this pH centric concept, a new therapeutic concept and selective targeting of cancer treatment has emerged, that can act both as a metabolic mediator of apoptosis and in the overcoming of multiple drug resistance (MDR).
Interestingly, the abnormalities of intracellular alkalization along with extracellular acidification is characteristic of all types of solid tumors and leukemic cells and are now accepted to be a fundamental and selective hallmark of malignancy. Therefore, a treatment strategy developed along this concept could be relevant to all cancers.
During the past decades we have contributed intensively to uncovering the relevance of pH in tumors and developing this new paradigm in oncology. Promising results have also been achieved during the recent years in both basic and translational studies, and as a result this approach is beginning to receive important attention regarding its application to bedside oncological treatment (“the cutting edge” in the evolution of clinical oncology).
The main therapeutic aim of the pH-centric paradigm and its hydrogen ion dynamics in translational and bedside oncology is the induction of a proapoptotic selective intracellular acidification of cancer cells using
- different membrane-bound inhibitors of proton transport and
- other non-proton transport derived cellular acidifiers.
This would reverse the selective cancer proton reversal (CPR) of malignant cells and tissues and consequently induce a selective intracellular acidification and simultaneously and increase in tumoral interstitial pH. At the same time, this would inhibit the Warburg effect and act as an antiglycolytic measure, thus controlling cancer growth and the metastatic process.
This perspective represents a rational approach to cancer therapeutics encompassing all stages of cancer development at the same time and it has the potential of being selectively exploited in the treatment of many, if not all, malignant solid tumors and leukemias.
The concerted use of PTIs (proton transport inhibitors) excl. PPIs (proton pump inhibitors) in pharmacological dosages in all types of tumors was suggested by Harguindey et al., in 2009 and has been actualized in 2017.
Next steps and efforts are now directed to finding the pharmacological and pharmacokinetics of the PTIs and PPIs, as well as the effective dosages. This requires extensive research.
Some of the clinical experience and the next steps to be taken have been recently considered in full in a recently published book (see reference: An Innovative Approach to Understanding and Treating Cancer: Targeting pH. From Etiopathogenesis to New Therapeutic Avenues).
As a customer of MCS Formulas, you will support this research project to achieve the following:
- Identifying the most suitable re-purposed drugs and natural extracts to inhibit proton pumps and transporters, including pharmacological and pharmacokinetics studies to indicate effective dosages. With this, the goal is to selectively acidify cancer cells and inhibit the export of protons that acidify the tumor micro-environment.
- Implement this pH centric strategy in clinical settings, on compassionate basis first, and possible clinical trials as a second step, in line with the approach suggested by our team in multiple previous publications (see a sample in the list of references).
Harguindey, S.; Stanciu, D.; Devesa, J.; Alfarouk, K.; Cardone, R.A.; Polo Orozco, J.D.; Devesa, P.; Rauch, C.; Orive, G.; Anitua, E., et al., Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases. Semin. Cancer Biol. 2017, 43, 157-179. [http://doi.org/10.1016/j.semcancer.2017.02.003].
Harguindey, S.; Reshkin, S.J.; Orive, G.; Arranz, J.L.; Anitua, E., Growth and trophic factors, pH and the Na+/H+ exchanger in Alzheimer’s disease, other neurodegenerative diseases and cancer: new therapeutic possibilities and potential dangers. Curr Alzheimer Res 2007, 4, 53-65.
Harguindey, S.; Orive, G.; Cacabelos, R.; Hevia, E.M.; de Otazu, R.D.; Arranz, J.L.; Anitua, E., 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). Neuropsychiatr. Dis. Treat. 2008, 4, 1073-1084.
Harguindey, S.; Reshkin, S.J., “The new pH-centric anticancer paradigm in Oncology and Medicine”; SCB, 2017. Semin. Cancer Biol. 2017, 43, 1-4. [http://doi.org/10.1016/j.semcancer.2017.02.008].
Harguindey, S.; Polo Orozco, J.; Alfarouk, K.O.; Devesa, J., Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies. Int. J. Mol. Sci. 2019, 20. [http://doi.org/10.3390/ijms20174278].
Harguindey, S.; Alfarouk, K.; Orozco, J.P.; Hardonniere, K.; Stanciu, D.; Fais, S.; Devesa, J., A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer Based upon Its Hydrogen Ion Dynamics. Int. J. Mol. Sci. 2020, 21. [http://doi.org/10.3390/ijms21031110].
Alfarouk, K.O.; Verduzco, D.; Rauch, C.; Muddathir, A.K.; Adil, H.H.; Elhassan, G.O.; Ibrahim, M.E.; David Polo Orozco, J.; Cardone, R.A.; Reshkin, S.J., et al., Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience 2014, 1, 777-802. [http://doi.org/10.18632/oncoscience.109].
Spugnini, E.P.; Sonveaux, P.; Stock, C.; Perez-Sayans, M.; De Milito, A.; Avnet, S.; Garcia, A.G.; Harguindey, S.; Fais, S., Proton channels and exchangers in cancer. Biochim. Biophys. Acta 2015, 1848, 2715-2726. [http://doi.org/10.1016/j.bbamem.2014.10.015].
Daniel, C.; Bell, C.; Burton, C.; Harguindey, S.; Reshkin, S.J.; Rauch, C., The role of proton dynamics in the development and maintenance of multidrug resistance in cancer. Biochim. Biophys. Acta 2013, 1832, 606-617. [http://doi.org/10.1016/j.bbadis.2013.01.020].
Spugnini, E.P.; Citro, G.; Fais, S., Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J. Exp. Clin. Cancer Res. 2010, 29, 44.
Harguindey, S.; Arranz, J.L.; Wahl, M.L.; Orive, G.; Reshkin, S.J., Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res. 2009, 29, 2127-2136.
Koltai T, Reshkin S, Harguindey S. An Innovative Approach to Understanding and Treating Cancer: Targeting pH. From Etiopathogenesis to New Therapeutic Avenues. 1st Edition Authors: Academic Press/Elsevier. January 2020. Pp 1-574.