Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders
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About this ebook
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
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Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders - Lucia Morbidelli
volume.
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
Fe² +
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 (Fe² +) 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 modifications and genome-wide epigenetic alterations. NO can activate or amplify tumor-suppressing effects acting in several antioncogenic pathways, for example, activating p53 or suppressing epigenetic modifications that can suppress metastasis and chemoresistance. NO can act as a protumorigenic agent, for example, via metabolic hypoxia, S-nitrosation of certain cell proteins, irregular epigenetic modifications, increased inflammation processes, and reprogramming the tumor microenvironment metabolism [12].
NO acts as a modulator of the tumor microenvironment and reprogramming stromal nonmalignant cells to support tumor progression. In addition, NO affects mitochondrial physiology, exerting concentration-dependent effects on the mitochondrial respiration, ATP formation, cytochrome c release, and the generation of reactive oxygen and nitrogen species. At low concentrations, NO reversibly inhibits complex IV of the respiratory chain (cytochrome oxidase) through binding to its copper center. It also inhibits a segment of complex II, without promoting cytochrome c release. In contrast, at high concentrations, NO promotes autoxidation of ubiquinol with the concomitant increased production of superoxide, hydrogen peroxide, and peroxynitrite. These reactive species may damage complexes I and II, impairing ATP synthesis, leading to the release of cytochrome c and promotion of apoptosis [13–16].
Different classes of enzymes contain cysteines in their active sites that might undergo S-nitrosation, which can inhibit enzymatic activities. Examples are cathepsin B (lysosomal proteolytic enzyme), aldolase (glycolysis), gamma-glutamylcysteine synthetase glutathione, and glyceraldehyde-3-phosphate dehydrogenase (glycolysis and gluconeogenesis) [17]. Antiapoptotic proteins such as B-cell lymphoma 2 (Bcl-2) and FLICE-inhibitory protein (FLIP) [18, 19] are also targets of S-nitrosation. FLIP is a key regulator of the extrinsic pathway of apoptosis; this antiapoptotic protein prevents procaspase 8 from recruiting subsequent apoptosis inducers [20]. Bcl-2 is a key protein of the intrinsic pathway of apoptotic cell death, which forms heterodimers with proapoptotic proteins and inhibits the formation of the transition pore of mitochondrial permeability and cytochrome c release [21]. The upregulation of cathepsin B expression has been reported in some types of cancer characterizing a tumor phenotype with increased invasiveness and metastatic potential [22], and its inactivation may contribute to the reduction of metastatic capacity and tumor