Nitric Oxide in Health and Disease: Therapeutic Applications in Cancer and Inflammatory Disorders

By Benjamin Bonavida

Nitric Oxide in Health and Disease: Therapeutic Applications in Cancer and Inflammatory Disorders presents updated information on the chemistry, signaling of newly derived therapeutic nitric oxide donors/inhibitors, and their complexes in liposomes or nanospheres in both pre-clinical and clinical activities. The book discusses many examples of research related to the application of novel therapeutic compounds that focus on a chemical—nitric oxide—and its applications that have been shown to exert significant therapeutic activities against various resistant cancers unresponsive to current treatments and different inflammatory diseases which continue to require novel treatments.

This is a valuable resource for cancer researchers, oncologists, graduate students and researchers from medical and biomedical fields who want to know more about NO and its therapeutic applications in cancer and inflammatory diseases.

• Provides updated reviews on the chemistry and signaling of newly derived therapeutic nitric oxide (NO) donors/inhibitors and their complexes in liposomes or nanospheres in both pre-clinical and clinical activities
• Discusses the application of NO in monotherapy or in combination with conventional therapies in a variety of cancers and inflammatory diseases
• Encompasses real-world examples of recent research related to NO and cancer

• Language: English
• Publisher: Academic Press
• Release date: Apr 13, 2023
• ISBN: 9780443133435

Book preview

9780443133435_FC

Nitric Oxide in Health and Disease

Therapeutic Applications in Cancer and Inflammatory Disorders

First Edition

Lucia Morbidelli, PhD

Department of Life Sciences, University of Siena, Siena, Italy

Benjamin Bonavida, PhD

Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States

Jordi Muntané, PhD

Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville (IBiS), Seville, Spain

Table of Contents

Cover image

Title page

Copyright

Contributors

About the Editors

Preface

References

Highlights of the II international conference therapeutic applications of nitric oxide in cancer and inflammatory-related diseases

Conference Program

Part I: Development of NO donors and derivatives, and new delivery formations

Chapter 1: Nitric oxide and derivatives: Molecular insights and translational opportunities

Abstract

Conflict of interest

Introduction

Bioavailability/biotransformation of NO

Role of NO in regulating inflammation and other functions during normal physiological activities

Role of NO during inflammatory diseases, tumor microenvironment, and cancers progression

Current clinical trials of NO

Ying and Yang of nitric oxide studies: Immunosuppressive tumor microenvironment induced by the nitric oxide production

Conclusion

References

Chapter 2: Biomedical applications of polymeric nitric oxide (NO) donors

Abstract

Acknowledgment

Conflict of interest

Introduction

Nitric oxide detection

NO production in human body

NO-releasing small molecules

Polymeric NO donors

Biomedical applications

Conclusion and future perspectives

References

Part II: Nitric oxide pathway and cancer progression and therapy

Chapter 3: Therapeutic potential for coxib-nitric oxide releasing hybrids in cancer treatment

Abstract

Conflict of interest

Introduction

COX-2 and cancer

Hybrid drugs: NO-releasing COX inhibitors

NO-coxibs based on diarylpyrrole scaffold

Conclusions

References

Chapter 4: Targeting dimethylarginine dimethylaminohydrolase 1 to suppress vasculogenic mimicry in breast cancer: Current evidence and future directions

Abstract

Conflict of interest

Introduction

Vasculogenic mimicry: Molecular mechanisms and pathophysiological significance

Dimethylarginine dimethylaminohydrolase 1: Biology and role in vasculogenic mimicry

Effects of pharmacological DDAH1 inhibition on vasculogenic mimicry in TNBC

General considerations

References

Chapter 5: Cancer stem cells and nitric oxide

Abstract

Acknowledgments

Conflict of interest

Introduction

Cancer stem cells

Nitric oxide

Nitric oxide as a modulator of the tumor microenvironment

Expression of nitric oxide synthases in tumors

Studies concerning CSCs and NO

NO as a novel therapeutic target in cancer

Conclusion

References

Chapter 6: Inducible nitric oxide synthase 2 (NOS2) and antitumor γδ-T cells

Abstract

Acknowledgments

Conflict of interest

Introduction

Cancer immunotherapies

Gamma delta T (γδ-T) cells

INOS/NOS2 expression

NOS2 and γδ-T cells

γδ-T cells in cancer immunotherapy

Perspectives

References

Chapter 7: The regulation of the programmed death ligand 1 (PD-L1) by nitric oxide in breast cancer: Immunotherapeutic implication

Abstract

Acknowledgments

Conflict of interest

Introduction

Evasion of cancer cells from CD8 T-cell–mediated immunotherapy: Role of PD-L1/PD-1 interactions

Programmed death ligand 1

Reversal of resistance to CMI by checkpoint inhibitors

Regulation of PD-L1 expression on cancer cells

Regulation of PD-L1 expression by nitric oxide (NO)

Inhibitors of NO and inhibition of PD-L1: Restoration of cancer cell response to CD8 T-cell–mediated immunotherapy

Remarks and perspectives

References

Chapter 8: Pepper fruit, as a nutraceutical food, shows antiproliferative activity against tumor cells and it is potentiatied by nitric oxide (NO)

Abstract

Conflict of interest

Acknowledgments

Introduction

Pepper fruit as a potential source of antitumoral compounds

Ripening and NO boost the nutritional properties of pepper fruits

Pepper fruits show antiproliferative activity on tumor cells

Conclusions

References

Part III: Nitric oxide donors and cardiovascular and metabolic diseases

Chapter 9: Nitric oxide (NO) donors in kidney damage and diseases

Abstract

Conflict of interest

Acknowledgments

Introduction

Physiological role of nitric oxide in the kidneys

Applicability and limitations of NO donors

Conclusions

References

Chapter 10: Nitric oxide resistance in type 2 diabetes: Potential implications of HNO donors

Abstract

Acknowledgments

Conflict of interest

Introduction

Evidence of NO• resistance in T2DM

Nitroxyl (HNO)

HNO donation, Angeli’s salt, and NO• resistance in T2DM

Conclusion and perspectives

References

Chapter 11: Inhaled nitric oxide (iNO) administration in intubated and nonintubated patients: Delivery systems, interfaces, dose administration, and monitoring techniques

Abstract

Conflict of interest

Inhaled nitric oxide in intubated patients

Inhaled nitric oxide in nonintubated patients

Inhaled nitric oxide administration in clinical practice

References

Chapter 12: Inhaled nitric oxide (iNO): Clinical applications in critical care medicine, delivery devices, and measuring techniques

Abstract

Conflict of interest

Introduction

NO sources

References

Chapter 13: Mechanistic insights on the role of nitric oxide in ischemia-reperfusion injury

Abstract

Conflict of interest

Introduction

Nitric oxide derivatives

Nitric oxide pathophysiology in ischemic reperfusion injury

Signaling pathways mediated by nitric oxide involved in ischemia-reperfusion injury

Conclusion

References

Part IV: Nitric oxide derivatives in ocular diseases

Chapter 14: Effect of nitric oxide inhibitors in retinitis pigmentosa

Abstract

Acknowledgments

Conflict of interest

Nitric oxide (NO) in the retina

Retinitis pigmentosa

Nitric oxide inhibitors

Nitric oxide inhibitors in retinitis pigmentosa

Conclusion

References

Chapter 15: Advances in the discovery of novel agents for the treatment of glaucoma: The role of nitric oxide donors

Abstract

Conflict of interest

Introduction

Carbonic anhydrase inhibitors as antiglaucoma agents

Carbonic anhydrase inhibitor: NO donor hybrids

Prostaglandin receptor agonists as antiglaucoma agents

PG agonists: NO donor hybrids

Nitric oxide donors per se

Conclusions

References

Conclusions and future perspectives

References

Index

Copyright

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Contributors

Eda Acikgoz     Department of Histology and Embryology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey

Maurizio Anzini     Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy

Maria Camila Suarez Arbelaez     Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Bhaskar Arora     Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

Himanshu Arora

Desai Sethi Urology Institute

John P Hussman Institute for Human Genomics

The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Zahra Bahadoran     Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Lorenzo Berra

Harvard Medical School

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital

Respiratory Care Department, Massachusetts General Hospital, Boston, MA, United States

Mariangela Biava     Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Rome, Italy

Benjamin Bonavida     Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States

Katherine Campbell     Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Antolín Cantó     Department of Biomedical Sciences, Faculty of Health Sciences, Institute of Biomedical Sciences, Cardenal Herrera-CEU University, CEU Universities, Valencia, Spain

Bastien Cautain

Department of Screening and Target Validation, Fundación MEDINA, Granada, Spain

Evotec – University Paul Sabatier Toulouse III, Toulouse, France

Carla Speroni Ceron     Department of Biological Sciences, Institute of Exact and Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil

Sara Consalvi     Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Rome, Italy

Francisco J. Corpas     Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Estación Experimental del Zaidín, CSIC, Granada, Spain

Priyadarsi De

Polymer Research Centre

Centre for Advanced Functional Materials, Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, India

José Pérez del Palacio     Department of Screening and Target Validation, Fundación MEDINA, Granada, Spain

Aleyna Demir     Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey

Caridad Díaz     Department of Screening and Target Validation, Fundación MEDINA, Granada, Spain

Gabriel Tavares do Vale     Minas Gerais State University (UEMG), Passos, Minas Gerais, Brazil

Bijan Safaee Fakhr     Department of Emergency and Intensive Care, San Gerardo Hospital, Monza, Italy

Fakiha Firdaus     Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Asghar Ghasemi     Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Stefano Gianni     Department of Anesthesia and Intensive Care Medicine, Niguarda Ca' Granda Hospital, Milan, Italy

Antonio Giordani     Formerly Rottapharm (Monza, Italy) at the Present Consultant, Pavia, Italy

Salvador González-Gordo     Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Estación Experimental del Zaidín, CSIC, Granada, Spain

Amarjot Kaur Grewal     Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

Julie-Ann Hulin     Discipline of Clinical Pharmacology, College of Medicine and Public Health and Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA, Australia

Khosrow Kashfi     Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, United States

Heena Khan     Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

Manish Kumar

Polymer Research Centre

Centre for Advanced Functional Materials, Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, India

Braian Ledesma     Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Brayden K. Leyva     Department of Physiological Sciences, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States

Katie Lin     Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, United States

Rosa López-Pedraja     Department of Biomedical Sciences, Faculty of Health Sciences, Institute of Biomedical Sciences, Cardenal Herrera-CEU University, CEU Universities, Valencia, Spain

Arduino A. Mangoni

Discipline of Clinical Pharmacology, College of Medicine and Public Health and Flinders Health and Medical Research Institute, Flinders University

Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, SA, Australia

Samuele Maramai     Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy

Javier Martínez-González     Department of Biomedical Sciences, Faculty of Health Sciences, Institute of Biomedical Sciences, Cardenal Herrera-CEU University, CEU Universities, Valencia, Spain

María Miranda     Department of Biomedical Sciences, Faculty of Health Sciences, Institute of Biomedical Sciences, Cardenal Herrera-CEU University, CEU Universities, Valencia, Spain

Parvin Mirmiran     Department of Clinical Nutrition and Human Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Maria Silena Mosquera     Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Arindam Mukherjee     Centre for Advanced Functional Materials, Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, India

Gulperi Oktem     Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey

José M. Palma     Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Estación Experimental del Zaidín, CSIC, Granada, Spain

Paola Patrignani     Department of Neuroscience, Imaging and Clinical Sciences, and Center for Advanced Studies and Technology (CAST), School of Medicine, G. D’Annunzio University, Chieti, Italy

Soumya Paul

Polymer Research Centre

Centre for Advanced Functional Materials, Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Nadia, West Bengal, India

Bruna Pinheiro Pereira     Federal University of Alfenas (UNIFAL), Alfenas, Minas Gerais, Brazil

Giovanna Poce     Department of Chemistry and Technologies of Drug, Sapienza University of Rome, Rome, Italy

Simone Regina Potje     Minas Gerais State University (UEMG), Passos, Minas Gerais, Brazil

Farah Rahman     Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Carmen Ramos     Department of Screening and Target Validation, Fundación MEDINA, Granada, Spain

Emanuele Rezoagli

School of Medicine and Surgery, University of Milano-Bicocca

Department of Emergency and Intensive Care, San Gerardo Hospital, Monza, Italy

Marta Rodríguez-Ruiz     Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture, Estación Experimental del Zaidín, CSIC, Granada, Spain

Antonietta Rossi     Department of Pharmacy, School of Medicine and Surgery, Federico II University of Naples, Naples, Italy

Mario Saletti     Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy

Amparo Sánchez-Fideli     Department of Biomedical Sciences, Faculty of Health Sciences, Institute of Biomedical Sciences, Cardenal Herrera-CEU University, CEU Universities, Valencia, Spain

Thakur Gurjeet Singh     Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India

Claudiu T. Supuran     University of Florence, Neurofarba Department, Section of Pharmaceutical and Nutraceutical Chemistry, Florence, Italy

Aysegul Taskiran     Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey

Sara Tommasi

Discipline of Clinical Pharmacology, College of Medicine and Public Health and Flinders Health and Medical Research Institute, Flinders University

Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, SA, Australia

Francisca Vicente     Department of Screening and Target Validation, Fundación MEDINA, Granada, Spain

Lashika Weerakoon     Discipline of Clinical Pharmacology, College of Medicine and Public Health and Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA, Australia

About the Editors

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Prof. Lucia Morbidelli’s present position is Associate Professor of Pharmacology at the Department of Life Sciences, University of Siena, Italy.

Prof. Morbidelli’s research experience is within the pharmacology of angiogenesis and microcirculation by means of a plethora of in vitro and in vivo models. Her background is based around the definition of the role of nitric oxide and prostanoid pathways in the process of physiological and tumor angiogenesis. She contributed to characterizing the activity of synthetic molecules and natural bioactives as pro- or antiangiogenic strategies. In the last decade, she has focused her attention on the gaseous transmitters nitric oxide and hydrogen sulfide by characterizing their activity in the maintenance of endothelial survival and functionality or as antitumor agents.

Prof. Morbidelli is author of over 170 scientific publications in peer reviewed journals, reviews, and chapters in books on the molecular, biochemical, and cellular aspects of angiogenesis and endothelial pharmacology.

Prof. Morbidelli was Guest Editor of the Special Issue of Pharmacological Research Drugs and druggable signaling in angiogenesis and of the Special Issue of Molecules on Natural products as preventive or therapeutic tools for angiogenesis related diseases. Together with Dr. Benjamin Bonavida, she was editor of the book Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders, published by Elsevier. In 2021, she edited the book Antiangiogenic drugs as chemosensitizers in cancer therapy by AP/Elsevier.

In addition to her scientific production, Prof. Morbidelli’s international collaborations are related to participation in the COST Action BM1005 European Network on Gaseoustransmitters (2012–2015) and as member responsible for pharmacological countermeasures of the ESA topical team Tissue Healing in Space: Techniques for promoting and monitoring tissue repair and regeneration (since 2017) and Pharmacological Countermeasures (since 2021).

Prof. Morbidelli’s current research topics are related to: (1) defining new targets within the tumor microenvironment responsible for the control of tumor angiogenesis; (2) the identification of drugs and medical devices (natural extracts, nutraceuticals) to recover endothelial and tissue function following injury, or disease conditions related to inflammation and oxidative stress, or unloading conditions.

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Dr. Benjamin Bonavida, PhD, is currently a distinguished research professor at the University of California, Los Angeles (UCLA). His research career, thus far, has focused on basic immunochemistry and cancer immunobiology. His research investigations have ranged from the mechanisms of cell-mediated killing, sensitization of resistant tumor cells to chemo-/immunotherapy, characterization of resistant factors in cancer cells, cell signaling pathways mediated by therapeutic anticancer antibodies, and characterization of a dysregulated NF-κB/Snail/YY1/RKIP/PTEN loop in many cancers, which regulates cell survival, proliferation, invasion, metastasis, and resistance. He has also investigated the role of nitric oxide in cancer and its potential antitumor activity. Many of the above studies are centered on the clinically challenging features of cancer patients’ failure to respond to both conventional and targeted therapies. The development and activity of various targeting agents, their modes of action, and their resistance are highlighted in many refereed publications.

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Prof. Jordi Muntané’s scientific career has been devoted to the study of the relevance of oxidative and nitrosative stress in cell proliferation and death in different experimental models and clinical settings involving acute hepatocellular injury and hepatocellular carcinoma. He studied the time-, dose-, and compartment-dependent impact of nitric oxide (NO) in cell death, as well as its involvement in the cytoprotective properties of classical antioxidants, prostanoids, and alpha-tocopherol in liver injury. The antitumoral properties of NO has also been demonstrated using NO-donors and nitric oxide synthase type III (NOS3) overexpression in in vivo and in vitro models. The NO-dependent posttranslational protein modifications induced by NOS3 overexpression was related to a drastic alteration of redox status and reduction of cell proliferation and induction of apoptosis in liver cancer cells. The relevance of NO-dependent posttranslational downregulation of cell death receptors to the antitumoral properties of the recommended molecular therapies for patients with advanced hepatocellular carcinoma, such as the tyrosine kinase inhibitor sorafenib, has also been studied. Furthermore, sorafenib altered the redox cellular status and reduced Nrf2-regulated genes such as thioredoxin-1 that appear to play a relevant role during the induction of caspase-3 in HepG2 cells.

Prof. Muntané coorganized with Prof. Benjamin Bonavida the Fourth International Workshop on Nitric Oxide in Cancer held in Sevilla, March 13–14, 2015. The meeting addressed various topics, including NO, mutagenesis, carcinogenesis, tumor promotion and tumor growth; NO regulation of cell death pathways; NO and proliferation and epithelial-mesenchymal transition; regulation of immune response by NO; antitumoral activity of NO-based releasing strategies: preclinical studies; and antitumoral activity of NO-based releasing strategies: clinical trials.

The Second International Conference Therapeutic Applications of Nitric Oxide in Cancer and Inflammatory-related Diseases was held on March 3–5, 2022, in Seville, Spain, coorganized by Prof. Jordi Muntané, Prof. Lucia Morbidelli, and Prof. Benjamin Bonavida. The state of the art in new applications of NO and derivatives was reported, as well as the engineering of various NO complexes that showed specific targeting.

Preface

Special issue Therapeutic applications of nitric oxide and derivatives

Nitric oxide (NO) is a small and gaseous signaling molecule that plays a vital role in numerous physiological processes, the disturbances of which are involved in different pathologies. The regulation of NO generation has important clinical applications. The different approaches for the therapeutic applications of NO are described in this volume. The chapter by Ledesma et al. [1] describes the impact of NO derivatives such as diazeniumdiolates (NONOates), S-nitrosothiols, NO hybrid drugs, NO-NSAIDs, S-nitroso-hybrid drugs, and zoolites, the effectiveness of which is actually tested in nearly 100 clinical trials. All dimensions of healthcare can be affected or potentially improved by the discovery of NO-based strategies, and highly relevant to this is the development of suitable carriers allowing tight dosage and target-specific NO delivery. The chapter by Paul et al. [2] reports that the polymeric NO donors are more advantageous than small molecular NO donors, as they provide additional control, including multifunctionality and stimuli-based NO release.

The tumor microenvironment results from the pivotal cross-talks among tumor cells, stromal cells, and the altered extracellular matrix, which functionally impacts the induction or progression of cancer cells. During the last three decades an increasing body of evidence has supported the involvement of chronic inflammation in all stages of tumorigenesis, tumor growth, and spread. In this regard, Giordani et al. [3] highlight the relevance of cyclooxygenase-2 (COX-2) and PGE2-derived products regarding tumor growth and tumor immune evasion. NO-donor COX-2 inhibitors can be effective therapeutic agents for cancer treatment, either in combination with immune checkpoint (PD-1/PD-L1) inhibitors or with standard chemotherapy. The pathophysiological and clinical significance of vasculogenic mimicry, an alternative neovascularization process involving the formation of vessel-like networks directly by the tumor cells, is especially important in triple negative breast cancer. Mangoni et al. [4] describe the promising agents being developed to inhibit dimethylarginine dimethylaminohydrolase (DDAH1), which is responsible for the removal of endogenous NO synthase (NOS) inhibitors, thus allowing vasculogenic mimicry in triple negative breast cancer.

Taskiran et al. [5] reported that cancer stem cells (CSCs) present in the tumor microenvironment are thought to be the main reason for the ineffectiveness of conventional cancer therapies including surgery, radiotherapy, and chemotherapy. The regulation of CSC-derived NO can be a suitable approach for regulating chronic inflammation in the tumor microenvironment, pro-tumorigenic activities of cancer-associated fibroblast (CAFs), drug resistance, invasion, and metastasis. Leyva et al. [6] reported on the unbalanced pro-oncogenic and pro-immunosuppressive activities of inflammatory cells that impact tumor progression. Moreover, the polarization of gamma delta T (γδ-T) cells from anti- to immunosuppressive Th17 phenotype largely related to NOS2 overexpression might be successfully regulated by NOS2 or NO inhibitors, promoting antitumor activities and the inhibition of tumor growth.

Lin et al. [7] discussed the development of immune checkpoint regulators that have been a vital breakthrough in cancer therapy. The use of the FDA-approved monoclonal antibodies directed against PD-L1 or PD-1 to block the inactivation of CD8 T cells results in significant killing of tumor cells and tumor inhibition. Interestingly, the expression of inducible NOS2 is related to PD-L1 overexpression in tumor cells. They also suggest that NO-based therapeutic interventions may restore the activity of the antitumor CD8 T cells. Fruits and vegetables contain bioactive compounds, such as vitamins, polyphenols, carotenoids, terpenoids, and alkaloids. Their content is, in most cases, improved during ripening or through the treatment of fruits with exogenous NO gas. Consequently, numerous fruits and vegetables can be considered, not only as nutritional vehicles, but also as nutraceutical foods, as discussed by Palma et al. [8].

NO is a key vascular mediator that allows adequate functional homeostasis of all organs and tissues. In particular, NO dysfunction is associated with alteration of renal hemodynamics. The review by Tavares Do Vale et al. [9] contributes to the understanding of the therapeutic potential of NO-regulatory drugs in the regulation of kidney function and derived diseases. Bahadoran et al. [10] review cardiovascular dysfunctions that are widely associated with chronic diseases that impact the survival of patients. The lack of responsiveness to NO of myocardium, vasculature, platelets, skeletal muscle, and vascular smooth muscle is a major risk for the development of cardiovascular events. They propose that nitroxyl (HNO) can circumvent the NO resistance associated with type 2 diabetes mellitus. The infusion of NO is also useful to treat neonates with persistent pulmonary hypertension and as a rescue strategy for the treatment of severe hypoxemia as a consequence of chronic pulmonary hypertension.

The study by Stefano et al. [11] defines the clinical conditions of treatments and the monitoring of blood oxygenation and methemoglobin concentration during NO infusion in order to ensure an adequate tissue oxygenation. Bijan et al. [12] review cost-effective methods to produce infused NO. The methods primarily used to measure the amount of infused NO delivered to the patient are very relevant in the clinical setting. Their proposal is to make it more cost-effective, making the procedure available worldwide. The impact of NO donors and/or inhibitors regulating oxidative stress and inflammatory response during acute brain damage during ischemic stroke is also addressed in the study by Arora et al. [13].

NO modulates visual transduction and maintains a normal visual function in the retina, also acting positively as a vasodilator agent implicated in ocular blood flow control under normal situations. Altered NO generation is related to different pathologies. Moreover, low NO generation is related primarily to glaucoma, while an excess of NO is related to retinitis pigmentosa, as reviewed by Cantó et al. [14]. In this setting, although drugs interfering with aqueous humor secretion (e.g., adrenergic agonists/antagonists, carbonic anhydrase inhibitors) and with its outflow from the eye (e.g., prostaglandin analogs, Rho kinase inhibitors and NO donors) are in clinical use, Supuran [15] reviews the recently approved prostaglandin-NO donor hybrids (such as latanoprostene bunod) and the Rho kinase inhibitors that have allowed the advancement of new therapeutic opportunities for the pharmacological management of this disease.

In conclusion, the volume Therapeutic Applications of Nitric Oxide and Derivatives provides a comprehensive description of new advancements at the frontier of knowledge that will allow a greater understanding of the impact of NO and its effectiveness for the management of patients suffering from cancer, stroke, cardiovascular diseases, and visual alterations.

Jordi Muntané

References

[1] Ledesma B., Firdaus F., Mosquera S., Campbell K., Farah Rahman M.P.H., Reddy R., Arora H. Nitric oxide and derivatives: molecular insights and translational opportunities.

[2] Paul S., Kumar M., Mukherjee A., De P. Biomedical applications of polymeric nitric oxide (NO) donors.

[3] Giordani A., Poce G., Consalvi S., Maramai S., Saletti M., Rossi A., Patrignani P., Biava M., Anzini M. Therapeutic potential for coxib-nitric oxide releasing hybrids in cancer treatment

[4] Mangoni A.A., Hulin J.-A., Weerakoon L., Tommasi S. Targeting dimethylarginine dimethylaminohydrolase-1 to suppress vasculogenic mimicry in breast cancer: current evidence and future directions.

[5] Taskiran A., Demir A., Acikgoz E., Oktem G. Cancer stem cells and nitric oxide.

[6] Leyva B.K., Bonavida B. Inducible nitric oxide synthase 2 (NOS2) and anti-tumor γδ-T cells.

[7] Lin K., Bonavida B. The regulation of the programmed death ligand 1 (PD-L1) by nitric oxide in breast cancer: immuno-therapeutic implication.

[8] Palma J.M., del Palacio J.P., Rodríguez-Ruiz M., González-Gordo S., Díaz C., Ramos C., Cautain B., Vicente F., Corpas F.J. Pepper fruit as a nutraceutical food with anti-proliferative activity against tumor cells potentiated by nitric oxide (NO).

[9] Do Vale G.T., Pereira B.P., Potje S.R. Ceron C.S. Nitric oxide (NO) donors in kidney damage and diseases.

[10] Bahadoran Z., Mirmiran P., Kashfi K., Ghasemi A. Nitric oxide resistance in type 2 diabetes: potential implications of HNO donors.

[11] Stefano G., Berra L., Emanuele R. Inhaled nitric oxide (iNO) administration in intubated and non-intubated patients: delivery systems, interfaces, dose administration, and monitoring techniques.

[12] Bijan S.F., Berra L., Emanuele R. Inhaled nitric oxide (iNO): clinical applications in critical care medicine, delivery devices and measuring techniques.

[13] Arora B., Khan H., Grewal A.K., Singh T.G. Mechanistic insights on role of nitric oxide in ischemia-reperfusion injury.

[14] Cantó A., Martínez-González J., López-Pedraja R., Sánchez-Fideli A., Miranda M. Effect of nitric oxide inhibitors in retinitis pigmentosa.

[15] Supuran C.T. Advances in the discovery of novel agents for the treatment of glaucoma: the role of nitric oxide donors.

Highlights of the II international conference therapeutic applications of nitric oxide in cancer and inflammatory-related diseases

It was with great pleasure and honor that we welcomed the II International Conference Therapeutic Applications of Nitric Oxide in Cancer and Inflammatory-Related Diseases that was held at the Institute of Biomedicine of Seville on March 3–5, 2022. The meeting was organized within the activities of the International Society for NO and Cancer (ISNOC, https://isnoc.org). Over 45 international scientists, either on-site or on-line, participated in this meeting and fostered with their expertise the current progress in the field of therapeutic applications of nitric oxide (NO).

The aim of the conference was to promote quality research and discuss the latest developments and innovations in NO-based drugs or NO-generating systems in the treatment of cancer and other inflammatory-related disorders. The workshop also expands on its translational implications in the diagnosis, prognosis and therapy of diseases. Briefly, the conference was organized to meet the following goals that, in our opinion, were achieved successfully:

(1)To discuss novel biochemical and molecular advances of NO implications in the pathophysiology of cancer and other diseases and their response to various treatments.

(2)To explore different options that could be employed to materialize the potential of targeting NO signaling for novel therapies.

(3)To facilitate scientific and collaborative interactions among the participants and encourage the establishment of lasting professional relationships among researchers investigating the role of NO in physiopathology.

Although each participant gave a special input to the success of the congress, undoubtedly, the contributions of the world-renowned experts on NO-based therapeutics have fulfilled the above goals.

Dr. Dennis J. Stuehr (Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, United States), in his keynote lecture entitled Hemeproteins, NO, and their relationships in cancer, presented an update on what is known about the intracellular heme trafficking during hemeprotein maturation, including his laboratory’s investigations in identifying the proteins involved in heme delivery, their mechanisms of action, and how the processes may be regulated. Different aspects of cancer are influenced by several hemeproteins, including the NO synthases, soluble guanylyl cyclase, NADPH oxidases, tryptophan and indoleamine dioxygenases, myoglobin, and hemoglobin. A new role for NO in regulating the intracellular heme allocations was presented.

Dr. David A. Wink (National Cancer Institute, Frederick, United States), in the keynote lecture NO-based therapeutic intervention in cancer, discussed the role of NO in tumor biology at the chemical, biochemical, and cellular levels to explore potential new strategies, based on the assumption that NO and other small redox-reactive molecules promote cancer progression. His research goals are focused on the identification of redox-related mechanisms and biomarkers expressed during chronic inflammation as they relate to cancer progression and poor clinical outcome.

Other highlights of the conference included the following advances that are briefly discussed below:

•Myoglobin-dependent decreased NO bioavailability and regulation of metabolism result in the attenuation of pro-tumorigenic signaling. Ongoing studies are delineating the exact mechanisms by which myoglobin regulates metabolic signaling and may offer a potential therapeutic avenue to attenuate tumor progression (presented by Dr. Sruti Shiva, University of Pittsburgh, Pittsburgh, United States).

•Up-to-date findings regarding NO signaling in cardiovascular health and disease were discussed. Some of the latest paradigms underlying the successes (or failures) of clinical applications of NO-based therapeutics in cardiovascular diseases were reported, highlighting the interest in measurements of nitrosylated hemoglobin as a biomarker for diagnostics and treatment tailoring (presented by Dr. Jean-Luc Balligand, Institut de Recherche Experimentale et Clinique (IREC) and Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium).

•Different polymeric nanoparticles that have been specifically designed to deliver anticancer drugs and to image specific tissues were discussed for their advanced applications. The delivery of NO was presented using these nanoparticles for the treatment of liver fibrosis and neuroblastoma, demonstrating a synergistic effect when NO is combined with chemotherapeutic drugs for the treatment of multidrug resistance in cancer. Further, the synthesis of new hybrid organic/inorganic nanomaterials, based on iron oxide, gold, and gadolinium, were reported for use as MRI contrast agents (presented by Dr. Cyrille Boyer, Australian Centre for NanoMedicine or CAN, and Centre for Advanced Macromolecular Design or CAMD, School of Chemical Engineering, University of New South Wales, Sydney, Australia).

•Photoresponsive polypeptide nanomedicines were discussed regarding their rational design for efficient NO gas delivery and cancer therapy (presented by Dr. Chang-Ming Dong, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China).

•Dimethylarginine dimethylaminohydrolase, a metabolic enzyme responsible for the processing of endogenous inhibitors of the NOS pathway, is essential for triple negative breast cancer cells to undertake vasculogenic mimicry, a hallmark of malignancy and therapy escape. The current evidence and future directions related to targeting dimethylarginine dimethylaminohydrolase isoform 1 to suppress vasculogenic mimicry in cancer were discussed (presented by Dr. Arduino A. Mangoni, Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Bedford Park, Australia).

•The advances in the discovery of novel agents for the treatment of glaucoma, a neuropathic disease characterized by increased intraocular pressure, were presented. NO donors play a relevant role in developing novel antiglaucoma agents, due to the involvement of this gas-transmitter in relevant ocular physiological processes, affording interesting new opportunities for the pharmacological management of this disease (presented by Dr. Claudiu T. Supuran, Department of Neuroscience, Psychology, Drug Area and Child Health University of Florence, Florence, Italy).

•The role of the gasotransmitter hydrogen sulfide was demonstrated by analyzing the value of sulfur nutraceuticals against cardiovascular inflamm-aging, a condition characterized by features common to many cardiovascular diseases accompanied by endothelial dysfunction. Experimental data were presented on erucin, the isothiocianate deriving from Eruca sativa Mill., which showed protective cardiovascular effects against vascular inflammation, endothelial dysfunction, and hypertension (presented by Dr. Alma Martelli, Department of Pharmacy, University of Pisa, Italy).

•The roles of NO in retinal pathologies were reported in relation to the high reactive tissue environment. Three different retinal degenerative disorders were considered: diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Although the data are contrasting, the experimental use of NOS inhibitors seems protective (presented by Dr. María M. Miranda, Department of Biomedical Sciences, University CEU Cardenal Herrera, Alfara del Patriarca, Valencia, Spain).

•The modulation of neurovascular coupling (NVC) in the brain by NO and its relationship with cognitive enhancement were addressed. By developing innovative tools for in vivo assessment of NVC, it was shown that neuronal NO along the NMDA receptor-nNOS-NO pathway acts as a direct mediator of the communication between neurons and local microvessels. The functionality of NVC is key for cognitive performance and becomes impaired during aging and age-associated neurodegeneration, notably Alzheimer’s disease. In vivo experimental data support that the redox interaction of nitrite/ascorbate/NO functionally coupled to neuronal activation in NVC, and rescue from impaired NVC, results in enhancement of cognitive performance (presented by Dr. João Laranjinha, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal).

•The role of iNOS and NO in regulating inflammation in neurodegenerative disease was reported. Nitration strongly increased Abeta’s propensity to aggregate and also made it harder to degrade and digest by microglia. In in vivo seeding models of cerebral amyloidosis, NO-mediated nitration of the Abeta increased overall deposition. Data were provided suggesting that NO may also exert harmful effects during the course of neurodegenerative disease. Its use as a therapeutic or its inhibition should be titrated in time, dose, and site of action (presented by Dr. Michael T. Heneka, Luxembourg Centre for Systems Biomedicine-LCSB, University of Luxembourg, Luxembourg).

•NO-mediated neuroinflammatory pathways have been considered as treatment targets in neurodegeneration. In addition to nitration reactions, nonenzymatic and irreversible glycation signaling has been implicated as an underlying pathway that promotes protein (i.e., Abeta) misfolding via the generation of advanced glycation end-products (AGE). Following activation of specific receptors recognizing AGEs (RAGE), further oxidative stress and production of cytokines induce an upregulation of inflammatory mediators. The direct interactions between NO-mediated neuroinflammation and RAGE signaling pathways were documented (presented by Dr. Joern R. Steinert, Division of Physiology, Pharmacology and Neuroscience, Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom).

•NOS and COX inhibition augment immune polarization and improve survival in radiotherapy. The possibility that NSAIDs and NOS inhibitors could be new approaches to improve radiation and immunotherapy efficacy was discussed (presented by Dr. Lisa A. Ridnour, National Cancer Institute, Frederick, United States).

•The state of the art and future directions of nanomedicine allied to NO donors in cancer therapy was discussed. NO-releasing engineered nanoparticles can have direct toxic effects on tumor cells, or can promote cancer cell sensitization for traditional cancer treatments, with reversion of multidrug resistance. The recent progress in the cytotoxicity (tumoral and nontumoral cell lines) of NO-releasing nanomaterials and the in vivo biocompatibility of NO-releasing nanoparticles were highlighted and discussed (presented by Dr. Amedea B. Seabra, Nanomedicine Research Unit, Federal University of ABC, Santo André, Brazil).

•The role of NO in macrophage immunometabolism was dissected. The elevated lactate levels in tumors can transcriptionally reprogram tumor-associated macrophages into immunosuppressive cells, promoting tumor growth and progression. The expression, signaling, and function of receptors expressed by innate immune cells in the context of cancer was discussed in relation to immunometabolism. Data showing the dissection of the biochemical mechanisms underlying activation-induced metabolic changes in innate immune cells were demonstrated (presented by Dr. Daniel W. McVicar, National Cancer Institute, Frederick, United States).

•The fascinating hypothesis of a fourth gasotransmitter, selenium and hydrogen selenide, besides being an essential micronutrient, was demonstrated, opening up research to new frontiers (presented by Dr. Alex Dyson, Institute of Pharmaceutical Science, and Centre for Pharmaceutical Medicine Research King’s College London, London, United Kingdom).

•The active principles present in pepper fruits during their maturation were characterized, along with the role of NO in fruit ripening. Based on the potential therapeutic effects of pepper fruit bioactive principles, the question arises whether NO could potentiate the antitumoral activity of pepper fruit extracts (presented by Dr. José M. Palma, Department of Biochemistry, Molecular and Cell Biology of Plants, Estación Experimental del Zaidín, CSIC, Granada, Spain).

•The design of conventional anticancer drugs complexed with a NO-releasing moiety was verified. NO-releasing gemcitabine was experimentally demonstrated to work as a new weapon against pancreatic cancer (presented by Dr. Chiara Riganti, Department of Oncology, University of Torino, Torino, Italy).

The last session of the meeting included a roundtable in which speakers presented their opinions on the aspects highlighted in the meeting regarding the impact of NO and the NO-based drugs for the management of patients in cancer and related-inflammatory diseases.

As a closing remark, we, as organizers, sincerely hope that this symposium served as an international platform for meeting researchers from all around the world, widened professional interactions, and created new opportunities for research collaborations. We have set high expectations on this series of NO meetings to be established on a regular basis and that it will attract global participants intent on sharing, exchanging, and exploring new avenues of the NO implications in human diseases and the latest developments in novel therapies.

Lucia Morbidelli (co-organizer)

The symposium program is enclosed in the following pages.

Conference Program

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Part I

Development of NO donors and derivatives, and new delivery formations

Chapter 1: Nitric oxide and derivatives: Molecular insights and translational opportunities

Braian Ledesmaa; Fakiha Firdausa; Maria Silena Mosquerab; Katherine Campbella; Farah Rahmana; Maria Camila Suarez Arbelaeza; Himanshu Aroraa,c,d    a Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

b Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States

c John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States

d The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States

Abstract

Nitric oxide (NO), a small, gaseous signaling molecule, plays a vital role in numerous processes such as hemodynamic maintenance, immune responses, and neurotransmission. Synthesized by nitric oxide synthase (NOS) in human tissue, NO can act as an electron donor or acceptor and thus participate in physiologic redox reactions. At low concentrations, NO plays a role in the regulation of immune responses with downstream effects including inducing inflammation, propagation of the cellular immune response, and direct cytotoxicity. Overproduction of NO at high concentrations results in DNA damage, inhibition of DNA repair, excess proliferation, and angiogenesis. Thus, at the genetic level, NO can either be cytoprotective or be cytotoxic, allowing scientists to harness the power of NO as an agent of future therapeutic strategy in cancer, cardiovascular disease, epilepsy, type II diabetes and others. The promising pharmaceutical future of NO is demonstrated in the fact that there are nearly 100 clinical trials focusing on NO as the primary target of interest. While NO may be minuscule in nature, it’s roles, activities, and implications seem to be a microcosm of discovery waiting for the scientific community to understand.

Keywords

Nitric oxide; Inflammation; Tumor microenvironment; S-Nitrosilation; Tumor pathophysiology

Abbreviations

ACE angiotensin-converting enzyme

ADMA asymmetric dimethylarginine

BCG Bacillus Calmette-Guerin

ECAM endothelial cell adhesion molecule

Hb hemoglobin

HPLC high-performance liquid chromatography

IL-1i interleukin 1

L-NAME L-NG-nitro arginine methyl ester

LPS lipopolysaccharides

MDSC myeloid-derived suppressor cell

N2O3 dinitrogen trioxide

NF-kB nuclear factor kappa-beta

NO nitric oxide

NO2− nitrite

NO3− nitrate

NONOate diazeniumdiolates

NOS nitric oxide synthase

NSAIDs nonsteroidal antiinflammatory drugs

ONOO− peroxynitrite

oxyHb oxyhemoglobin

PAD peripheral artery disease

PCD primary ciliary dyskinesia

RBC red blood cell

RSNO S-nitrosothiol adducts

SNOAlb S-nitrosoalbumin

SNO-Cap S-nitrosocaptopril

SOD superoxide dismutase

TGF-β transforming growth factor-β

TNF tumor necrosis factor

Conflict of interest

No potential conflicts of interest were disclosed.

Introduction

Nitric oxide (NO) serves a multifaceted role in signaling and is implicated in a multitude of physiological mechanisms, including but not limited to hemodynamic homeostasis, immune responses, and retrograde neurotransmission [1,2]. This molecule also influences innumerable pathologic processes in the human body, from the mechanism of vasoconstriction and vasodilation to diseases and cancer. The versatility of nitric oxide can, in part, be attributed to its chemical properties: It is small, reactive, uncharged, and a free radical [3].

The history of nitric oxide (NO) traces back to Joseph Priestley in 1772, who first documented the gas in his experiment involving iron and brimstone [4]. Notably, Louis Ignarro, Robert F. Furchgott, and Ferid Murad won a Nobel Prize for their discoveries of NO as a molecular messenger in the cardiovascular system, paving a new path for therapeutics.

Aside from the functions that NO holds in physiology, this molecule can also be utilized as a therapeutic agent. Inhaled NO has been clinically employed in the management of a spectrum of cardiopulmonary diseases, including pulmonary hypertension in children and adults [5]. Furthermore, derivatives of NO, such as nitrogen dioxide and peroxynitrite, have been utilized for anticancer purposes [6]. In this chapter, we discuss the metabolism of NO, its role in physiological regulation, its use in ongoing clinical trials, and future potential avenues for this heterodiatomic molecule.

Bioavailability/biotransformation of NO

Nitric oxide (NO) is a gaseous signaling molecule synthesized in various mammalian organs by nitric oxide synthase (NOS). To date, three distinct isoforms have been identified, namely neuronal NOS (type I), inducible NOS (type II), and endothelial NOS (type III). Various cofactors critically influence NO synthesis like tetrahydrobiopterin, flavin mononucleotide, and flavin adenine dinucleotide, reduced thiols, endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), and substrate availability. Additionally, NOS I and III depend on calmodulin and Ca²+. The clearance of NO depends on its concentration. NO may react electrostatically to its target by electron gain or loss to form the nitrosyl anion NO− or NO+, the nitrosonium ion, respectively. The conversion of NO to NO+ is contributed by numerous factors, such as heme proteins like guanylate cyclase, enzymes such as catalase, xanthine oxidase and superoxide dismutase along with hemoglobin (Hb), or any high-energy free radicals such as the hydroxyl radical. NO is presumably charge neutral, which facilitates its free infusibility in aqueous solution and across cell membranes to travel significant distances via blood vessels.

The major immediate breakdown product of NO in human plasma is nitrite (NO2−). RBCs could take up plasma NO2−, where it is oxidized in a Hb-dependent manner to nitrate (NO3−), which may subsequently redistribute into plasma [7]. Another potential decomposition pathway for NO is its rapid interaction with superoxide anions to produce the