pH-Interfering Agents as Chemosensitizers in Cancer Therapy

Claudiu T. Supuran, Simone Carradori, Claudiu Supuran

• Publisher: Academic Press
• Year: 2020
• Print ISBN: 9780128207017
• eBook ISBN: 9780128209288
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

pH Interfering Agents as Chemosensitizers In Cancer Therapy, Volume Thirteen, provides a detailed overview of the chemosensitizers for the treatment of cancer spanning from biochemical and structural features to pharmacology and drug-design, including technological applications. The book is structured with innovative outlines and a distinction between experimental and clinical results. The continuous discovery and assessment of the role played by old/new synthetic drugs, natural compounds and technological applications has led to the urgent need of classification in terms of biological activity, mechanism of action, clinical outcomes, cancer cell lines sensible to the treatment, and potentialities to better orient research in this field.Moreover, all the aspects relevant for medicinal chemistry (drug design, structure-activity relationships, permeability data, cytotoxicity, appropriate statistical procedures, and molecular modeling studies) are strictly considered.- Presents a broad view of the topic according to a medicinal chemistry-based approach beyond syntheses and biological assays, focusing on SAR studies, chemoinformatic, drug targeting and molecular modeling- Explains the mechanism of action of the chemosensitizers by means of schemes and figures to facilitate comprehension- Discusses novel targets to explore new possibilities that enhance research in the field

Part I

General overview of the topic: An update

Chapter 1: Tumors and their microenvironment

Paola Chiarugi; Luigi Ippolito Laboratory of Tumor Microenvironment, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

Abstract

It is well acknowledged that tumors display extensive cellular and molecular heterogeneity. Despite of cell-intrinsic (genetic and epigenetic) changes, tumor cells evolve into high-grade malignancies, along with the tumor microenvironment representing a landscape of cellular and structural components. Malignant cells experience a dynamic and complex scenario of communications with nonmalignant stromal cells, recruited and/or corrupted in loco by tumor-derived soluble factors, cytokines, metabolites, and matrix-remodeling agents. Together with acidity and hypoxia, microenvironmental signals favor tumor progression and exacerbate malignant phenotype, from the tumor initiation to the metastatic spreading.

Keywords

Cancer hallmarks; Warburg hypothesis; Tumor microenvironment; Anoikis; Hypoxia; Acidosis; Cancer-associated fibroblastic cells

Abbreviations

CA carbonic anhydrase

CAF cancer-associated fibroblastic cell

CREB cAMP response element-binding protein

ECM extracellular matrix

EMT epithelial-mesenchymal transition

HIF hypoxia-induced factor

IFN interferon

IL interleukin

MAPK mitogen-activated protein kinase

MMP matrix metalloproteinase

NF-ĸB nuclear factor kappa-light-chain-enhancer of activated B cells

pHe extracellular pH

PI3K phosphoinositide 3-kinase

pRB retinoblastoma protein

Tc cytotoxic T cells

TGF transforming growth factor

Th helper T cells

TME tumor microenvironment

TNF tumor necrosis factor

Treg regulatory T cells

VEGF vascular endothelial growth factor

Conflict of interest

No potential conflicts of interest were disclosed.

Introduction

Hanahan and Weinberg have successfully summarized the main traits of cancer aggressiveness in their two seminal papers. They simply describe that the complexity of cancer biology can be condensed in a small number of fundamental principles that are biological capabilities shared by cancer cells during the multistep process of tumor formation and progression [1].

The hallmarks of cancer aggressiveness are:

• – Self-sufficiency in growth signals. Cancer cells have the ability to grow without hormonal signals, likely by producing these signals by themselves (autocrine signaling), by constitutively activating signaling pathways associated to hormones, or by silencing termination signals.
• – Evading growth suppressors. Cancer cells resist to inhibitory signals that might otherwise stop their growth (an event occurring in normal proliferative cells), eliminating tight control of cell division through tumor suppressor genes. This allows cell division also if DNA is damaged or during contact with other neighboring cells.
• – Evading apoptosis. Cancer cells lose the ability to activate a programmed cell death, a process known as apoptosis. Nevertheless, cells may become completely abnormal, they do not undergo apoptosis. Cancer cells are able to do so by altering the mechanisms to detect damages and circumventing cell cycle, or nutrient and adhesion checkpoints.
• – Limitless replicative potential. Cancer cells indefinitely proliferate. Cancer cells escape natural senescence and undergo immortalization, being apparently capable of indefinite growth and division. Cancer cells bypass the senescence barrier by manipulating telomerases to increase the length of telomeres or by disabling their pRB and p53 tumor suppressor proteins, with the consequent emergence of a genome alterations, strongly correlated with DNA damage to multiple genes controlling cell division (oncogenes) and tumor suppressors.
• – Sustained angiogenesis. Cancer cells stimulate the growth of blood vessels to supply nutrients for themselves. As a growing tumor requires new blood vessels to receive adequate oxygen and nutrients, cancer cells acquire the ability to orchestrate the machinery needed for a new vasculature by activating the so-called angiogenic switch, unbalancing the net production of proangiogenic factors over the antiangiogenic ones.
• – Tissue invasion and metastasis. Cancer cells are able to invade local tissue and spread to distant sites. Malignant tumors undergo a multistep process allowing (i) local invasion of these cells from the primary site into the surrounding tissues, then (ii) the intravasation and the consequent facing the harsh environment of the circulatory system, (iii) the extravasation and engraftment into a distant organ. Cancer cell motility is enhanced through activation of epithelial-mesenchymal transition (EMT) or mesenchymal-amoeboid transition, two epigenetic pathways allowing adaptations of motility styles to different tissue microenvironment.
• – Metabolic deregulation. Most cancer cells exhibit abnormal metabolic demands, fluxes, and bioenergetics, as revealed in the early twentieth century in the Warburg hypothesis (i.e., massive upload of glucose, which is diverted into glycolytic collateral pathways as well as in lactate fermentation, even under aerobic conditions). Recent advances showed a peculiar metabolic plasticity of cancer cells, beyond the glycolytic pathway. Such metabolic deregulation showed by cancer cells spans from different nutrients exploitation in a restricted environment, to the nutrient competition, until the epigenetic regulation exerted by metabolites such as succinate, fumarate, and 2-hydroxyglutarate (namely, oncometabolites).
• – Evading the immune system. Cancer cells are able to avoid immune-surveillance, the natural mechanism of cancer detection by the immune system. Indeed, cancer cells elicit a complex response driving immune effector cells inhibition, while sustaining Treg activation, with the final outcome to be hidden to the immune system.
• – Sustained inflammation. Cancers have been described as “wounds that do not heal,” mainly due to sustained local chronic inflammation, caused by recruiting several accessory populations within the neoplasm. Chronic inflammation has been correlated with sustained angiogenesis and inhibition of functional immune response, thereby explaining the role of inflammation in sustaining cancer aggressiveness. ECM (extracellular matrix), hypoxia end acidity are all environmental factors enhancing tumor inflammation, thereby concurring to increase cancer aggressiveness (see below).

The role of tumor microenvironment

It has been largely clarified that most of the hallmarks of cancer are allowed and sustained to varying degrees through contributions from different stromal cell types (Fig. 1).

Fig. 1 Contributions of activated/recruited stromal cells to the hallmarks of cancer. Most of hallmarks of cancer involve contributions by stromal cells of the tumor microenvironment. The stromal cells can be divided into three general classes, depicted here by their involvement in specific hallmarks.

Cellular and structural elements organize the so-called tumor microenvironment (TME) [2]. Whereas cancer had previously been viewed as a heterogeneous disease involving aberrant mutations in tumor cells, it is now evident that tumors are also heterogeneous because of nongenetic features, provided by the microenvironmental cellular and structural composition. Indeed, in response to evolving environmental conditions and oncogenic signals from growing tumors, TME dynamically changes over the course of cancer progression, underscoring the need to consider his influence on events, often spatially and temporally distant such as metastasis, and to understand how tumor cells drive the construction of their own niche. Indeed, the current conceptual model (Fig. 2) proposes that, in the course of tumor progression, cancer cells exert increasingly stronger influence over their microenvironment.

Fig. 2 Schematic view of tumor progression accompanied with stromal cells. Normal tissues are composed of the basement membrane and a layer of luminal epithelial cells. During neoplastic transformation, the epithelial cells are epigenetically and phenotypically altered and their number decreases, potentially due to degradation of the basement membrane, and transformed cells start to unlimitedly grow. At the same time, the number of stromal cells - including CAFs, immune, and endothelial cells—increases during the tumor development. The massive growth of tumor cells, together with their intensive re...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Cover Image Insert
• Aims and scope for series “Cancer sensitizing agents for chemotherapy”
• About the Series Editor
• Aims and Scope of the Volume
• About the Volume Editors
• Preface
• Contributors
• Part I: General overview of the topic: An update
• Part II: pH-Interfering agents as chemosensitizers
• Part III: Chemosensitizing agents: Computational tools and technological approaches
• Index