pH Deregulation as the Eleventh Hallmark of Cancer

1st Edition - June 30, 2023
Authors: Tomas Koltai, Larry Fliegel, Stephan J. Reshkin, Fatima Baltazar, Rosa Angela Cardone, Khalid Omer Alfarouk, Julieta Afonso
Language: English
Paperback ISBN:
9 7 8 - 0 - 4 4 3 - 1 5 4 6 1 - 4
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 1 5 4 6 2 - 1

pH Deregulation as the Eleventh Hallmark of Cancer presents key concepts about pH deregulation in a concise and straight-forward manner. The book discusses topics such as pH regula… Read more

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pH Deregulation as the Eleventh Hallmark of Cancer presents key concepts about pH deregulation in a concise and straight-forward manner. The book discusses topics such as pH regulation and metabolism, sodium hydrogen exchanger, monocarboxylate transporter, V-ATPase proton pump, carbonic anhydrases, and voltage gated sodium channels. In addition, it covers clinical and therapeutic implications and future perspectives. This is a valuable resource for researchers, oncologists, students and members of the biomedical and medical fields who want to learn more about the role of pH deregulation in cancer treatment.

pH deregulation can improve the outcome of classical treatments without adding toxicity to them, and the book shows that treating the pH peculiarities of cancer is simple and can be performed with existing drugs. Based on the classification of tumor malignancy in ten hallmarks, the authors put pH deregulation at the spotlight and separated from metabolic reprogramming due to its impact on all other hallmarks, proposing it as an additional characteristic to evaluate and fight cancer.

Cover
Title page
Table of Contents
Copyright
Dedication
Acknowledgment
Introductory words
Chapter 1: pH Regulation and metabolism: Basic concepts
Abstract
pH regulation
Concentration of protons ([H+]) and pH
Some basic definitions
pH homeostasis
What is the need for these different pH compartments?
Buffers
pH and enzymatic activity
Transport of substances and ions in and out of cells
The proton extruders
Metabolism
Antimetabolite
Cell respiration and metabolism
How does CO2 play an important role in acid-base balance?
In summary [25–28]
References
Chapter 2: The pH gradient in cancer: pH deregulation
Abstract
Historical background
Main participants of the pHtome
When does the pH inversion start?
How does the pHtome work
How do cancer cells survive in the acidic microenvironment?
Extracellular acidity: The origins
Extracellular acidity: The consequences
Intracellular alkalinity
Conclusions
References
Chapter 3: The pHtome
Abstract
Introduction
Why are there so many participants in the pHtome?
Can the pHtome be inhibited?
References
Chapter 3.1: Na+/H+ exchangers (NHEs)
Abstract
Introduction
Tissue and subcellular distribution
NHE's in breast and prostate cancer
Summary
References
Chapter 3.2: Voltage gated sodium channels (VGSCs)
Abstract
Structure (Figs. 1 and 2)
VGSCs in cancer
NaV1.5 and breast cancer
Clinical implications
Discussion
Other possible combinations
References
Chapter 3.3: Carbonic anhydrases (CAs)
Abstract
Introduction
Structure
Intracellular carbonic anhydrase II (CA II)
CA II in tumors
Inhibiting CAs
Conclusions
References
Chapter 3.4: The sodium bicarbonate cotransporter (NBC) family
Abstract
General overview
NBC protein structure, isoforms and tissue distribution
NBC in normal physiology: Role and regulation
NBC in disease: Role in the cancer pHtome
NBC expression in malignancy and clinical significance
Targeting NBC for cancer treatment
Conclusions
References
Chapter 3.5: Monocarboxylate transporters (MCTs) and lactate
Abstract
Lactic acid or lactate?
Role of lactate in cancer
MCT structure, function and role in cancer
MCTs as targets for cancer therapy
Lactate tracers for patient treatment monitoring
Conclusions
References
Chapter 3.6: The vacuolar type-ATPase proton pump
Abstract
Introduction
Structure
Function
V-ATPase proton pump in cancer
Proton pump inhibitors
The proton sink
Conclusions
References
Chapter 3.7: Voltage gated proton channel (Hv1)
Abstract
Introduction
Mechanism of action
Role in cancer
A hypothesis on how Hv1 works in cancer: The NOX2-Hv1 association
Inhibitors of Hv1
Conclusions
References
Chapter 4: Coordinated action of the pHtome: Integrating the cancer pH process
Abstract
Introduction
pHtome coordination
Rules of pH deregulation
Conclusions
References
Chapter 5: How pH deregulation favors the hallmarks of cancer
Abstract
A summary of the main concepts of the hallmarks of cancer
The hallmarks (eight hallmarks and two enabling characteristics) [1–5]
Sustaining proliferative signaling
Evading growth suppressors
Resisting cell death
Enabling replicative immortality
Inducing angiogenesis
Activating invasion and metastasis
Reprogramming energy metabolism
Evading immune destruction
Genome instability
Inflammation
Conclusions
References
Chapter 6: Deregulated pH: Therapeutic implications and treatment
Abstract
Introduction
pH-centered treatments
Hydroxycitrate and α-lipoic acid
Combination of lipoic acid and hydroxycitrate
Capsaicin
The pH-centered scheme
Discussion
Partial use of the scheme
Future perspectives
Conclusions
References
Chapter 7: Cancer metabolism and its interplay with pH
Abstract
Introduction
Cancer metabolism
Beyond Warburg
Centrality of glucose in cancer metabolism and alternative pathways
What comes first: The increase in intracellular pH or glycolysis?
Relationship mitochondria, glycolysis and pH
Carbon dioxide in pH gradient determination
Therapeutic targeting of the metabolism-pH relationship
Targeting tumor metabolism through mitochondria (Mito-booster agents)
Anti-tumoral actions of ALA
Conclusions
References
Chapter 8: pH and drug resistance
Abstract
Introduction
Increased efflux of drugs
Drug extrusion proteins
Relationship between MDR and pH
Further evidence of the relationship pH-MDR
Possible role of electric conductivity
Treatment scheme to target MDR
Mechanisms to increase drug access
Conclusions
References
Chapter 9: Membrane proton sensing potentiates the pro-tumoral effects of extracellular acidity
Abstract
Introduction
The pH sensing systems
Effects of AS-GPCRs
Therapeutic resistance
Increased anti-apoptotic proteins
Evidence of ASICs’ pro-tumoral behavior
Discussion
The controversies
Conclusions
References
Chapter 10: Final words
References
Index

Tomas Koltai

Tomas Koltai is Board Certified Specialist in Medical Oncology (1985), PhD in Chemistry (1997) and Master’s in Sciences in Molecular Oncology, University of Buenos Aires (2011). He has vast experience on cancer treatment at several positions: staff oncologist, Sanatorio Mater Dei, Argentina (1985-1990); Head of Oncology, Central Hospital of the Centro Gallego de Buenos Aires (1990-2000) and Medical Director, at the same institution (2000-2002); Head of the Department of Chemotherapy, National Social Services for Retirees, Argentina (2002-2014); Head of the Department of Oncology, Social Services of the National Food Workers Union, Argentina (2010-2014) and Medical Director at the same institution (2014-2016). He has authored several seminal publications on cancer and created the new “triple-edged cancer treatment”.

Affiliations and expertise

Former Medical Director, Hospital del Centro Gallego de Buenos Aires, Argentina

Larry Fliegel

Research in Dr. Fliegel’s laboratory investigates membrane proteins’ function, how intracellular pH is regulated and the role of Na+/H+ exchanger in human disease, especially heart disease and breast cancer. The work is funded by CIHR and other sources. Dr. Fliegel has published over 150 publications in numerous journals including J. Biological Chemistry, J. Molecular and Cellular Cardiology, Hypertension, Cancer Research, Basic Research in Cardiology and others. He has authored two books and served on several editorial boards of Journals and grant panels such as CIHR. His awards include a Killam Annual Professor Award (2009-10), a Tier one Basic Science Mentoring Award (2013), McCalla Research Professorship Award (2007) and Alberta Heritage Foundation for Medical Research Scientist Award (2006-2013).

Affiliations and expertise

Professor, Associate Chair, Department of Biochemistry, Faculty of Medicine, University of Alberta, Canada

Stephan J. Reshkin

Stephan Reshkin, PhD, is molecular biologist and Associate Professor at the University of Bari (Italy). Dr. Reshkin has published 108 scientific papers, several book chapters and co-authored An Innovative Approach to Understanding and Treating Cancer: Targeting pH (Elsevier, 2020). His main research interests are cancer cell and pancreatic ductal adenocarcinoma.

Affiliations and expertise

Associate Professor, Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Italy

Fatima Baltazar

Fátima Baltazar holds a degree in Pharmaceutical Sciences by the University of Coimbra (Portugal, 1991), a PhD by the University of Hull (UK, 1998) and has postdoctoral experience at the University of Minho (Portugal, 1998-2003). She is currently Associate Professor at the Medical School of University of Minho (Portugal). Fatima joined ICVS (Life and Health Sciences Research Institute) team in 2004 and she is currently Principal Investigator and Coordinator of the Surgical Sciences Research Domain (SSRD). She started her research on the Cancer field in 2005 and, in the last years, Fatima’s main research interest has been on cancer metabolism, focusing on the discovery of new prognostic metabolic biomarkers and cancer therapeutic targets, using human samples and suitable in vitro and in vivo cancer models. Fátima has published 104 international peer-reviewed research articles, 8 book chapters and she is also (co-)inventor on two national patent applications.

Affiliations and expertise

Associate Professor, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

Rosa Angela Cardone

Rosa Angela Cardone is currently Assistant Professor at the Department of Bioscience, Biotechnologies and Biopharmaceutics, Section of Physiology, University of Bari, Italy. She has a long-standing expertise in the pH deregulation and has extensively investigated its role in tumor transformation and malignancy.

Affiliations and expertise

Associate Professor, Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Italy

Khalid Omer Alfarouk

Khalid O. Alfarouk is currently Assistant Professor at Al-Ghad International Health Sciences Colleges, Al-Madinah Al-Munawarah, Saudi Arabia. His research focus is on cancer metabolism and pH in cancer.

Affiliations and expertise

Assistant Professor, Alfarouk Biomedical Research LLC, Temple Terrace, FL, USA; Hala Alfarouk Cancer Center, Khartoum, Sudan

Julieta Afonso

Julieta Afonso is currently Assistant Professor at Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho. Her research focus is monocarboxylate transporters.

Affiliations and expertise

Post-doctoral researcher, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal