An Innovative Approach to Understanding and Treating Cancer: Targeting Ph: from Etiopathogenesis to New Therapeutic Avenues

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AN INNOVATIVE
APPROACH TO
UNDERSTANDING
AND TREATING
CANCER:
TARGETING pH
From Etiopathogenesis to
New Therapeutic Avenues
Copyright
Contributors
Preface
Part I: Metabolism and pH physiopathology of cancer
1
Introduction
	Introductory words
	The basics
		The importance of pH in cancer
		The evolving concept of pH in cancer
			First phase
			Second phase
			Third phase
			Fourth phase
		Clinical implications
	The objectives of this book
	References
2
Cancer metabolism
	Introduction
	The Warburg effect
	The glycolytic phenotype
		Targeting glycolytic enzymes in cancer
		The lactate shuttle122
		The pentose phosphate pathway
	The lipogenic phenotype
		Fatty acid synthase
		The metabolism of invadopodia
	Glutaminolytic phenotype
	Serine phenotype
	The acid-base balance in malignant tumors
	The ROS problem
		The pH paradigm and metabolic changes in cancer
	Multitargeted attack on tumor metabolism
	Conclusions
	References
3
The pH-centered paradigm in cancer
	Part I: The pH paradigm in cancer. Introduction
		Common view points or perceptions of cancer origin and progression
		The pH paradigm in cancer: Extracellular acidity, intracellular alkalinity and the pH gradient
	Effects of pH gradient inversion in cancer
		Intracellular alkalinity
		Extracellular acidity
		The pH gradient inversion
	The hypoxia-pH gradient inversion relationship
		Can hypoxia act as a carcinogenic agent by itself independently of genetic instability?
		Hypoxia and pH gradient inversion
		Clinical impact of the pH centered paradigm in cancer therapeutics
		Some examples of how increasing pHe improves therapeutic results
		Conclusions Part I
	Part II: Why and how does the pH-centered paradigm develop in cancer?
		The role of hypoxia in cancer metabolism and growth
		Metabolic switch and pH abnormalities
		Mechanisms that create an acidic extracellular matrix and an alkaline intracellular milieu
		New therapeutic directions derived from the pH-centered paradigm
		Why is pHe so acid and pHi alkaline in cancer cells?
		Tumor heterogeneity and the lactate shuttle in cancer
		Cell death and pH
		Clinical implications of the acid-base regulation in cancer
		Glioblastoma as an ideal test of concept
		pH evolution in cancer: Its relation with cellular metabolism
		Conclusions Part 2
	References
4
Lactic acid and its transport system
	Introduction
	Pro-tumoral activities of lactic acid
		Lactate contributes to extracellular space (ECS) acidity
		Lactate is a source of energy for OXPHOS cells: The lactate shuttle
	Lactate shuttle and pH
	Clinical implications of the lactate shuttle
		Lactate enhances tumor cell motility and migration
		Lactate is a signaling molecule
		Lactate has immunosuppressive effects in tumors
		Lactate induces pro-angiogenic effects
		Lactate levels have a high correlation with metastasis and also promote metastasis
		Lactate has pro-inflammatory effects
	The lactate transport system
	CD147/basigin/EMMPRIN/gp42
	Therapeutic considerations
	Conclusions
	References
5
The sodium hydrogen exchanger 1 (NHE1)
	pH-tome: Introduction
	NHE1
		Function and structure
		NHE1 structure (Fig. 1).
	Factors that modify NHE1 activity
		Stimulation of NHE1 activity: Mechanism of action
		NHE1 and the metabolic hallmarks of cancer
		Mechanisms of NHE1 expression
		NHE1 activity in cancer
		Therapeutic implications
	Conclusions
	References
6
Voltage gated sodium channels
	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
	References
7
Carbonic anhydrases
	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
		Breast cancer
		Clinical trials
		Clinical and therapeutic implications
	Topiramate
	Celecoxib
	Conclusions
	References
8
The vacuolar H+ ATPase proton pump
	Introduction
	Structure, regulation and function
		Function of the V-ATPases
	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
	References
9
The sodium bicarbonate cotransporter (NBC) family
	Introduction
	NBC structure and isoforms
	NBC structure
	NBC modulation in normal tissues
	Regulation of NBCs (Fig. 3)
		NBCs in disease
		Cancer
		NBC and cancer
		NBC and migration
			Should NBC be inhibited for cancer treatment?
	Conclusions
	References
10
pH gradient inversion, aquaporins and cancer
	Introduction
	The different kinds and roles of aquaporins
	pH and aquaporins
	Aquaporines structure
	Aquaporin trafficking
	Aquaporins regulation
	Aquaporins in disease
	Aquaporins in cancer
	Analysis of AQPs pro-cancer activities
		Aquaporins in migration
			The pH theory
			Reciprocal role of pH and AQPs
		Aquaporins in invadopodia
		AQPs and angiogenesis
		AQPs and apoptosis
		AQPs and lactic acid extrusion
		AQPs and pH
			Intracellular pH
			Extracellular pH
		AQP1 and CO2
	Importance and evidence of different AQPs in cancer
		Conclusions on AQP1
		Conclusions on AQP3
		Conclusions on AQP4
	Comments on the contents of the tables
	AQP inhibitors
	To what extent is aquaporin inhibition clinically possible?
	Conclusions
	References
11
Migration, invasion, invadopodia, and the inversion of the pH gradient
	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: Targeting the migration/ECM degradation/ invasion axis
			Which are the main players in invadopodia formation?
			Targeting Src
	Clinical implications
	Conclusions
	References
12
The Specificity protein 1 (Sp1) transcription factor
	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
	References
Part II: Therapeutics
13
The inverted pH gradient in cancer: Pharmacological interventions. Part I
	Introduction
		Does this have any practical importance?
	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
	References
14
Pharmacological interventions part II
	NHE1 inhibitors
		Introduction
			Amiloride
				Cancer, amiloride and exosomes
				Drawbacks of amiloride
			Cariporide (HOE 642), eniporide and other derivatives
			Compound 9t
		Troglitazone and other PPARγ agonists
	Voltage gated sodium channel (VGSC) inhibitors
		Tetrodotoxin (TTX)
		Phenytoin (diphenylhydantoin)
		Carbamazepine (CAR)
		Valproic acid (VAL)
		Topiramate (TOP)
		Flunarizine (FLU)
		Interactions between anticonvulsivants and chemotherapeutic drugs
			Ranolazine
			Polyphenols
			Riluzole (RIL)
			Local anesthetics
	Proton pump inhibitors (PPIs)
	Conclusions
	References
15
Pharmacological interventions part III
	Transporter blockers
		MCT inhibitors
			Lonidamine (LON)
				Lonidamine (LON) and multidrug resistance (MDR)
				Evidence of LON's anti-MDR effects
					In breast cancer cell lines (MCF-7)
					Other cell lines
			Quercetin (QUER)
		Enzyme inhibitors
			Carbonic anhydrase inhibitors (CAI)
		Drugs with non fully identified mechanisms
			3-Bromopyruvate (3BP)
		Miscelaneous mechanisms of acidification
			Salinomycin (SAL)
			Niclosamide
			Disulfiram
			Lipophilic statins (simvastatin, atorvastatin)
			Diclofenac
			Perillyl alcohol (POH)
			Urocanic acid
			Silymarin
			Ciprofloxacin (cipro)
			5-Nonyloxytryptamine (5-NOT) and related intracellular pH acidifiers
		Extracellular alkalinization
	Conclusions
	References
16
Pharmacological interventions part IV: Metabolic modifiers
	2-Deoxy-d-glucose (2DG)
		2-Deoxyglucose and cell growth in vitro and in vivo
			In vitro
			In vivo
		The mechanism of intracellular acidification
		Clinical experience
		2DG and multidrug resistance (MDR)
		Other uses and effects of 2DG
		Associations with 2DG
		2DG and chemotherapeutics
		Why is 2DG a poor anti-cancer drug?
		Discussion
		Conclusions
	Metformin
		Metformin as an anti-cancer drug
		Molecular mechanisms of metformin
			Endometrial cancer
				Thyroid cancer
				Colorectal cancer
				Breast cancer
		Metformin and the LKB1/AMPK axis
		Context-dependent activity of metformin
		Non-contextual effects of metformin
		Conclusions
	Dichloroacetate
		Mechanism of action
		Experimental evidence of DCA activity in cancer
		DCA and some interesting associations
			DCA and metformin
			DCA and COX2 inhibitors
			DCA and lipoic acid
			DCA and 2D-deoxy glucose (2DG)
			DCA and sulindac
			Mitaplatin
		A mechanism to ``make DCA work´´ in cancer
		Side effects
		Clinical cases
		Against DCA
		DCA responders and DCA non-responders
		Conclusions
	Cimetidine in cancer: A different kind of drug
		Introduction
			Mechanisms of cimetidine's anti-tumoral action
	References
17
New horizons on pH regulators as cancer biomarkers and targets for pharmacological intervention
	Introduction
	Monocarboxylate transporters
		Expression and prognostic value
		Exploitation as therapeutic targets
		Clinical studies
	Carbonic anhydrases
		Expression and prognostic value
		Exploitation as therapeutic targets
		Clinical studies
	Sodium proton exchangers
		Expression and prognostic value
		Exploitation as therapeutic targets
		Clinical studies
	Vacuolar-type H+-ATPases
		Expression and prognostic value
		Exploitation as therapeutic targets
		Clinical studies
	Anion exchangers
		Expression and prognostic value
		Exploitation as therapeutic targets
		Clinical studies
	Conclusions
	References
18
Treating the pH gradient inversion
	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
	References
19
Metronomic anti-angiogenesis: The ideal companion of pH-centered treatments
	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?
		Other possible components of the antiangiogenic scheme
		Resistance to antiangiogenic treatment
		The antiangiogenic schedule
	Clinical experience
	Discussion
	Conclusions
	References
20
Preventing metastasis with pH regulation
	Introduction
	The metastatic risk can be reduced
		The metastatic cascade
	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
		Amiloride
		Celecoxib
		Aspirin
		Extracellular acidity treatment
		Topiramate
	Clinical cases
	Conclusions
	References
21
Vacuolar-ATPase proton pump inhibition in cancer therapy: Veterinary and human experience
	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
	References
	Further reading
22
Taking advantage of cancers pH alterations: pH-sensitive nanoparticles
	Introduction
	The problems of chemotherapy
		The bioavailability of the chemo drug (CD) at the tumor site
		An adequate penetration into the malignant cell
		Toxicity to normal cells
	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
		Radiosensitizing NPs
		The making of an NP
			Polymer-based drug delivery
			Micelle-based drug delivery
	Clinical implications
	Conclusions
	References
23
Summary and final conclusions
	What we saw from the mountain top
	The present
	The future
	What this book tried to show
		Molecular level
		Therapeutic level
		Future perspectives
Abbreviations
Index
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