Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders

Lucia Morbidelli, Benjamin Bonavida

• Publisher: Academic Press
• Year: 2019
• Print ISBN:
  9780128165454
• eBook ISBN:
  9780128172797
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders presents updated reviews on the chemistry, signaling, pre-clinical and clinical activities on the role of nitric oxide donors/inhibitors used alone and in combination with other therapeutic agents for the treatment of a variety of diseases. This book examines various studies related to the application of novel therapeutic NO (donors/inhibitors) compounds in the treatment of various cancers. These studies have been shown to exert significant therapeutic activities against various cancers and various inflammatory diseases such as rheumatoid arthritis, Crohn's disease, allergies, and asthma, where no current effective therapies exist. Pathologies based on functional and structural vascular alterations are also taken into consideration. Edited and written by internationally renowned experts in the field of novel therapeutics for cancer, this book is a valuable source for cancer researchers, medical scientists, clinicians, clinical pharmacologists, and graduate students. - Provides readers with a clear overview of the recent findings and references as well as summaries, significant molecular pathways, and conclusions - Discusses new ideas proposed and makes suggestions for further investigations that will advance the field - Presents introductory and summary information on the contributions of the field, all the findings of the studies discussed, and projects future goals for research

Part 1

Applications of Nitric Oxide in Cancer

Chapter 1

Nitric Oxide-Releasing Engineered Nanoparticles: Tools for Overcoming Drug Resistance in Chemotherapy

Amedea B. Seabra^⁎,†; Milena T. Pelegrino^⁎,†; Letícia Ferraz^⁎; Tiago Rodrigue^⁎; Wagner J. Fávaro^†,‡; Nelson Durán^{⁎,†,‡ ⁎} Center for Natural and Human Sciences (CCNH), Nanomedicine Research Unit (NANOMED), Universidade Federal do ABC (UFABC), Santo André, Brazil
^† NanoBioss, Universidade Estadual de Campinas, Campinas, Brazil
^‡ Laboratory of Urogenital Carcinogenesis and Immunotherapy, Department of Structural and Functional Biology, Universidade Estadual de Campinas, Campinas, Brazil

Abstract

The endogenous free radical nitric oxide (NO) plays pivotal physiological and pathophysiological functions, including in cancer biology. NO donors have been extensively used for anticancer activities, and more recently, the combination of NO donors and nanomaterials has been shown to be a promising approach to generate controllable therapeutic concentrations of NO at the target site (tumor cells). Several important publications showed the promising uses of NO-releasing nanomaterials in increasing tumor perfusion, due to the improvement of the enhanced permeability and retention effect, allowing chemotherapeutic drugs to penetrate leaky tumor blood vessels. In this scenario, the coadministration of NO-releasing nanomaterials and chemotherapeutic drugs has emerged as a promising approach to realize the full clinical potential of NO in cancer therapy. Recently, an increasing number of reports have demonstrated that low concentrations of NO (those that if administrated alone would not be able to promote apoptosis) contribute to the reversal of multidrug resistance. Thus, this observation has motivated and inspired researchers to combine NO donors allied with nanomaterials for the improvement of chemotherapy. Therefore, this chapter describes the recent progress (last 3 years) in the design of different kinds of NO-releasing nanomaterials for cancer treatment. Most of these nanocarriers are able to release controllable amounts of NO on demand, upon light, pH, or wave exposure. In addition, the combination of NO-releasing nanomaterials with classical chemotherapeutic drugs in the treatment of cancer is also presented and discussed. The possible mechanisms of NO to sensitize tumor cells and the impact of nanomaterials in cancer treatment are also discussed. Finally, the perspectives and challenges in the design of efficient NO-releasing nanomaterials in cancer treatment in real clinical settings are highlighted.

Keywords

Nitric oxide donors; Nanomaterials; Nanomedicine; Cancer; EPR effect

Abbreviations

ADD adjudin

Alkynyl-JSK O²-(2,4-dinitrophenyl) 1-[4-(propargyloxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate

AMS amine-modified mesoporous silica

B16F10 mouse melanoma

Bcl-2 B-cell lymphoma 2

CaCO₃ calcium carbonate

CS chitosan

CT26 mouse colonic cancer cells

DETA diethylenetriamine

DOX doxorubicin

EPR enhanced permeability and retention

Fe^{2 +} ferrous ion

FLIP FLICE-inhibitory protein

GSH glutathione

GSNO S-nitrosoglutathione

HDPNs double-layered polymer nanoparticles

HepG2 human hepatocellular carcinoma

HMTNPs hollow mesoporous titanium dioxide nanoparticles

HT29 colon carcinoma cells

K562 human chronic myeloid leukemia

Lucena-1 a vincristine-resistant K562 cell line

MCF-7 breast cancer cells

MCF-7/ADR drug-resistant human breast cancer cells

MDR multidrug resistance

N₂O₃ peroxynitrite

NAP N-acetyl-d-penicillamine thiolactone

NIR near-infrared

NO nitric oxide

NO₃⁻ nitrate

NO-Dex hydrophobic nitrated dextran

NONOate diazeniumdiolates

NO-NPs NO nanoparticles

NOS nitric oxide synthase

NOx NO-related species

PEG polyethylene glycol

P-gp P-glycoprotein

RBS Roussin’s black salt, a photosensitive NO donor

ROS reactive oxygen species

SDT sonodynamic therapy

SH sulfhydryl groups

Si-DETA (3-trimethoxysilylpropyl)diethylenetriamine

SPION@hMSN superparamagnetic iron oxide-encapsulated mesoporous silica nanoparticles

TPGS D-α-tocopherol polyethylene glycol 1000 succinate

TPZ tirapazamine

UCNPs NaYF4:Yb,Eu upconversion

US ultrasound

Acknowledgments

Support from NanoBioss (MCTI), INOMAT (CNPq/MCTI), CNPq, and FAPESP.

We would like to thank Proof-Reading-Service.com Ltd for revising the text.

Conflict of Interest

No potential conflicts of interest were disclosed.

Introduction: Overview of Nitric Oxide in Cancer Biology

Nitric oxide (NO) is a free radical involved in several physiological and pathophysiological processes. It is a small-sized and uncharged molecule with a relatively high lipophilicity, which allows its diffusion through biological membranes without the need of membrane channels or receptors [1]. NO is involved in various physiological processes, such as the control of vascular tone, inhibition of platelet adhesion and aggregation, smooth muscle cell replication, immune responses, neuronal communication, wound healing, cell differentiation, and apoptosis [2]. Also, NO is a key molecule in the immune system, and it is considered important for the natural host defense against pathogens, such as bacteria, fungi, and viruses [3]. NO may bind with high affinity to the ferrous ion (Fe^{2 +}) and in the iron-sulfur centers of hemoproteins, and both copper and zinc are targets of NO actions [4]. Considering its properties and reactivity, the study of NO activities and the molecular pathways involving NO signaling would provide useful tools as diagnostics, therapeutics, and prognosis of different pathologies, including cancer [5].

In mammals, NO is enzymatically synthesized by the action of nitric oxide synthase (NOS) from the oxidation of the amino acid l-arginine to l-citrulline [6]. The protein family of NOS comprises inducible NOS, endothelial NOS, and neuronal NOS [7]. The first is calcium-independent and produces relatively high doses of NO for a longer period of time. These three NO isoforms may be involved in the process of proliferation or inhibition of tumor growth. High NO concentrations may be cytostatic or cytotoxic to tumor cells, whereas low NO concentrations may have the opposite effect and promote tumor growth [8, 9]. NO synthesized endogenously or donated by exogenous sources generates modifications in signaling proteins and, depending on its concentration, may present both angiogenic and genotoxic properties. NO can cause DNA damage. Peroxynitrite, which is formed from the reaction between NO and superoxide anion, can oxidize and nitrate DNA, causing breaks in the single strand of DNA by attacking the sugar-phosphate skeleton, and N₂O₃ can nitrosate amines, leading to the formation of N-nitrosamines [9, 10]. As a consequence of DNA damage, there is an accumulation of p53 in the cells and activation of poly (DNA ribose) polymerase, which in turn may induce apoptosis [9]. In fact, NO can inhibit tumor cell growth, leading to cell death by the apoptotic pathway [11]. The expression of NOS is associated with metabolic alterations, neoplasticity, angiogenesis, chemoresistance, and immune evasion. NO also regulates posttranslational protein modifi...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• About the Editors and Acknowledgements
• Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders
• Preface
• Part 1: Applications of Nitric Oxide in Cancer
• Part 2: Applications of Nitric Oxide in Inflammatory-Related Disorders
• Part 3: Abstracts (Presentations at Conference in Siena, October 2018)
• Index