An Innovative Approach to Understanding and Treating Cancer Targeting pH 1st edition by Tomas Koltai,Stephan Reshkin,Salvador Harguindey 9780128190593 0128190590

Part I: Metabolism and pH physiopathology of cancer

Chapter 1: Introduction

Abstract

Introductory words

The basics

The objectives of this book

Chapter 2: Cancer metabolism

Abstract

Introduction

The Warburg effect

The glycolytic phenotype

The lipogenic phenotype

Glutaminolytic phenotype

Serine phenotype

The acid-base balance in malignant tumors

The ROS problem

Multitargeted attack on tumor metabolism

Conclusions

Chapter 3: The pH-centered paradigm in cancer

Abstract

Part I: The pH paradigm in cancer. Introduction

Effects of pH gradient inversion in cancer

The hypoxia-pH gradient inversion relationship

Part II: Why and how does the pH-centered paradigm develop in cancer?

Chapter 4: Lactic acid and its transport system

Abstract

Introduction

Pro-tumoral activities of lactic acid

Lactate shuttle and pH

Clinical implications of the lactate shuttle

The lactate transport system

CD147/basigin/EMMPRIN/gp42

Therapeutic considerations

Conclusions

Chapter 5: The sodium hydrogen exchanger 1 (NHE1)

Abstract

pH-tome: Introduction

NHE1

Factors that modify NHE1 activity

Conclusions

Chapter 6: Voltage gated sodium channels

Abstract

Introduction

VGSCs and cancer

Sodium channel proteins and cancer

The location and relations of VGSCs in malignant cells

Different functions of α subunit and β subunit in relation to cancer

VGSC β subunit and cancer

Association of ion channel regulators

Clinical implications and conclusions

Chapter 7: Carbonic anhydrases

Abstract

Introduction

The CAIX gene

The chemical reaction catalyzed by CAs

Structure of membrane carbonic anhydrases

CA mediated mechanism of the pH inversion

Membrane carbonic anhydrases and cancer

Topiramate

Celecoxib

Conclusions

Chapter 8: The vacuolar H+ ATPase proton pump

Abstract

Introduction

Structure, regulation and function

PPs and cancer

V-ATPase proton pumps’ contributions to the pH paradigm in cancer development

Proton pump inhibition

Finding the appropriate PPI

The case for esomeprazole (ESO)

The case for pantoprazole (Panto)

The case for lansoprazole (Lan)

The case for omeprazole (Ome)

A proof of concept

Conclusions

Chapter 9: The sodium bicarbonate cotransporter (NBC) family

Abstract

Introduction

NBC structure and isoforms

NBC structure

NBC modulation in normal tissues

Regulation of NBCs (Fig. 3)

Conclusions

Chapter 10: pH gradient inversion, aquaporins and cancer

Abstract

Introduction

The different kinds and roles of aquaporins

pH and aquaporins

Aquaporine’s structure

Aquaporin trafficking

Aquaporins regulation

Aquaporins in disease

Aquaporins in cancer

Analysis of AQPs pro-cancer activities

Importance and evidence of different AQPs in cancer

Comments on the contents of the tables

AQP inhibitors

To what extent is aquaporin inhibition clinically possible?

Conclusions

Chapter 11: Migration, invasion, invadopodia, and the inversion of the pH gradient

Abstract

Cancer cell migration, invasion and metastasis

Migration and lamellipodia/podosomes vs invasion and invadopodia/invadosomes

Voltage gated sodium channels (VGSCs)

Formation of invadopodia

Invadopodia formation steps 1, 2 and 3

Invadopodia formation steps 4 and 5

Factors that induce invadopodia formation

pH and invasion

The NHE1-invadopodia-proteolysis relationship

Clinical implications

Conclusions

Chapter 12: The Specificity protein 1 (Sp1) transcription factor

Abstract

Introduction

Sp1 transcription factor is a pro-tumoral protein

Inhibiting Sp1

Why Sp1 down-regulation has a role in the targeting of the pH-tome?

Association of drugs

Conclusions

Part II: Therapeutics

Chapter 13: The inverted pH gradient in cancer: Pharmacological interventions. Part I

Abstract

Introduction

The importance of addressing the pH paradigm in cancer

Historical perspective

What comes first glycolysis or pH inversion?

Which is more important pHe or pHi?

Therapeutic approach

Cellular acidification

Attacking NHE1

Anticancer potential of NHE inhibitors

Reversing the altered pH gradient: Rational association of inhibitors

Conclusions

Chapter 14: Pharmacological interventions part II

Abstract

NHE1 inhibitors

Voltage gated sodium channel (VGSC) inhibitors

Proton pump inhibitors (PPIs)

Conclusions

Chapter 15: Pharmacological interventions part III

Abstract

Transporter blockers

Conclusions

Chapter 16: Pharmacological interventions part IV: Metabolic modifiers

Abstract

2-Deoxy-d-glucose (2DG)

Metformin

Dichloroacetate

Cimetidine in cancer: A different kind of drug

Chapter 17: New horizons on pH regulators as cancer biomarkers and targets for pharmacological intervention

Abstract

Acknowledgments

Introduction

Monocarboxylate transporters

Carbonic anhydrases

Sodium proton exchangers

Vacuolar-type H+-ATPases

Anion exchangers

Conclusions

Chapter 18: Treating the pH gradient inversion

Abstract

Introduction

The pH reversal drugs

The pH gradient inversion reversal scheme

The logic behind the scheme

Some practical issues with the scheme

Ancillary drugs

Conclusions

Chapter 19: Metronomic anti-angiogenesis: The ideal companion of pH-centered treatments

Abstract

Introduction

Cyclophosphamide (CTX)

Low dose metronomic cyclophosphamide: Clinical and experimental evidence (Table 1)

Low dose metronomic cylophosphamide: Mechanism of action (Table 2)

What is the best dose in metronomic chemotherapy?

Clinical experience

Discussion

Conclusions

Chapter 20: Preventing metastasis with pH regulation

Abstract

Introduction

The metastatic risk can be reduced

Metastasis prevention: When and how

The pre-metastatic niche

Cancer dormancy

Metastasis prevention treatment based on pH

Radiotherapy as a source of increased metastatic risk

Fundamentals of the preventive schedule

Clinical cases

Conclusions

Chapter 21: Vacuolar-ATPase proton pump inhibition in cancer therapy: Veterinary and human experience

Abstract

Introduction

Contribution of V-ATPases to cancer progression and chemoresistance

Anti-V-ATPase compounds

V-ATPase and acidic tumor pH in autophagy

Studies in murine models

Clinical evidence supporting the efficacy of PPIs as anticancer drugs

Conclusions

Chapter 22: Taking advantage of cancer’s pH alterations: pH-sensitive nanoparticles

Abstract

Introduction

The problems of chemotherapy

pH-sensitive NPs that release the drug in acidic sites

pH-sensitive NPs that release the drug inside the cell

NPs that can acidify the cytoplasm

NPs that deposit their load on the cell surface but do not let it enter the cell

Double release NPs

Multidrug release NPs

Clinical implications

Conclusions

Chapter 23: Summary and final conclusions

What we saw from the mountain top

The present

The future

What this book tried to show

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