Begell House Inc.
Critical Reviews™ in Oncogenesis
CRO
0893-9675
21
5-6
2016
Preface: Nitric Oxide and Cancer: Pathological and Therapeutic Aspects
v
10.1615/CritRevOncog.2017021472
Valentina
Rapozzi
Department of Medicine, University of Udine, 33100 Udine, Italy
Greta
Varchi
Italian National Research Council
Institute of Organic Synthesis and Photoreactivity Bologna, Italy
N/A
Highlights of the Fifth International Workshop on Nitric Oxide and Cancer
309-324
10.1615/CritRevOncog.2017021382
Valentina
Rapozzi
Department of Medicine, University of Udine, 33100 Udine, Italy
Claudia
Ferroni
Italian National Research Council, Institute of Organic Synthesis and Photoreactivity, Bologna, Italy
Greta
Varchi
Italian National Research Council
Institute of Organic Synthesis and Photoreactivity Bologna, Italy
nitric oxide
cancer
inflammation
GSNOR NO donors
NO conjugate
Nitric oxide (NO) is an endogenous molecule that performs key physiological signaling functions. The overall biological effect exerted by NO strongly depends on its concentration. Indeed, at a low concentration NO acts
as a signal transducer affecting many physiological processes, such as blood flow regulation, iron homeostasis, and neurotransmission, while at a high concentration it preferentially exerts cytotoxic effects. Gaining knowledge about the molecular pathways involved in the NO-tumor response represents a great scientific and clinical challenge for developing novel anticancer strategies based on either endogenous or exogenous NO regulation and induction. This review summarizes the most recent advances in the pathological and therapeutic roles of NO in cancer achieved by prominent experts in the field. In particular, the following topics are reviewed: the role of inducible nitric oxide synthase (iNOS) in chronic inflammation and tumorigenesis; the connection between NOS and IL-10 and their function in immunity at the tumor site; the role of NO in photodynamic therapy; and the role of S-nitrosylation in cancer. Finally, an overview of NO-mediated therapies for cancer treatment is provided, including iNOS inhibitors, NO-releasing compounds, and molecular conjugates and nanoparticles that induce NO formation upon irradiation with light.
Nitric Oxide and PGE-2 Cross-Talk in EGFR-Driven Epithelial Tumor Cells
325-331
10.1615/CritRevOncog.2017021204
Sandra
Donnini
Department of Life Sciences, Via A. Moro, 2, 53100, University of Siena, Siena, Italy
Lorenzo
Bazzani
Department of Life Sciences, University of Siena, Siena, Italy
Marina
Ziche
Department of Medicine, Surgery and Neurosceinces, University of Siena, 53100 Siena, Italy
Erika
Terzuoli
Department of Life Sciences, University of Siena, Siena, Italy
NO
PGE-2
EGFR
tumor growth
tumor angiogenesis
Nitric oxide (NO) exerts physiopathological effects based mainly on its concentration. Thus, it facilitates or inhibits cancer-promoting characteristics. This review discusses the role of NO and its network of partners
in tumor progression and angiogenesis: prostaglandin E 2 (PGE-2) and its producing enzymes, cyclooxigenase 2 (COX-2) and microsomal PGE synthase 1 (mPGES-1), and epidermal growth factor receptor (EGFR) signaling. Understanding the molecular mechanisms and cross-talk modulating NO effects by PGE-2 and EGFR and vice versa allows us to develop better therapeutic strategies for cancer treatment.
Review of Triple Negative Breast Cancer and the Impact of Inducible Nitric Oxide Synthase on Tumor Biology and Patient Outcomes
333-351
10.1615/CritRevOncog.2017021307
Elaine M.
Walsh
Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland
Galway, Galway, Ireland; Medical Oncology, Galway University Hospitals, Galway, Ireland
Maccon M.
Keane
Medical Oncology, Galway University Hospitals, Galway, Ireland
David A.
Wink
Cancer and Inflammation Program, Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland
Grace
Callagy
Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland
Galway, Galway, Ireland
Sharon A.
Glynn
Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland
triple negative breast cancer
TNBC
nitric oxide
molecular targets
EGFR
chemotherapy
platinum
taxanes
Triple negative breast cancers (TNBCs), which are defined as estrogen-receptor, progesterone-receptor, and HER2-receptor negative, account for 10–20% of breast cancers, and they are associated with early metastasis, chemotherapeutic resistance, and poor survival rates. One aspect of TNBC that complicates its prognosis and the development of new molecular therapeutic targets is its clinical and molecular heterogeneity. Herein we compare TNBC and basal cytokeratin–positive breast cancers. We examine the different TNBC molecular subtypes, based on gene expression profiling, which include basal-like, mesenchymal, and luminal androgen receptors, in the context of their biology and impact on TNBC prognosis. We explore the potential role of inducible nitric oxide synthase (iNOS) in TNBC tumor biology and treatment responses. iNOS has been shown to induce p53 mutation accumulation, basal-like gene signature enrichment, and transactivation of the epidermal growth factor receptor (EGFR) via S-nitrosylation, all of which are key components of TNBC biology. Moreover, iNOS predicts poor outcome in TNBC, and iNOS inhibitors show efficacy against TNBC when used in combination with chemotherapy. We discuss molecular targeted approaches, including EGFR, PARP, and VEGF inhibitors and immunotherapeutics, that are under consideration for the treatment of TNBC and what role, if any, iNOS may play in their success.
Role of Endogenous Nitric Oxide in Hyperaggressiveness of Tumor Cells that Survive a Photodynamic Therapy Challenge
353-363
10.1615/CritRevOncog.2017020909
Albert W.
Girotti
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226-3548, USA
NO
iNOS
iNOS inhibitors
photodynamic therapy
apoptosis resistance
hyperaggressiveness
Many malignant tumors exploit nitric oxide (NO) for a survival, growth, and migration/invasion advantage,
and also to withstand the cytotoxic effects of chemo- and radiotherapies. Endogenous NO has also been shown to antagonize photodynamic therapy (PDT), a unique minimally invasive modality involving a photosensitizing (PS) agent, PS-exciting light in the visible- to near-infrared range, and molecular oxygen. The anti-PDT effects of NO were discovered about 20 years ago, but the underlying mechanisms are still not fully understood. More recent studies in the author's laboratory using breast, prostate, and brain cancer cell lines have shown that inducible NO synthase (iNOS/NOS2) is dramatically upregulated after a PDT challenge using 5-aminolevulinic acid (ALA-) –induced protoporphyrin IX as the PS. The parallel increase in NO resulted not only in a greater resistance to cell killing but also in a striking increase in the growth and migration/invasion rate of surviving cells. These in vitro findings and their
recent recapitulation at the in vivo level are discussed in this article, along with how iNOS/NO's negative effects on PDT can be attenuated by the use of select iNOS inhibitors as PDT adjuvants.
Nitric Oxide's Contribution to Selective Apoptosis Induction in Malignant Cells through Multiple Reaction Steps
365-398
10.1615/CritRevOncog.2017021056
Georg
Bauer
Institute of Virology, Medical Center and Faculty of Medicine, University of Freiburg, Hermann-Herder Str. 11, D-79104 Freiburg, Germany
nitric oxide
peroxynitrite
hydroxyl radical
apoptosis
catalase
SOD
singlet oxygen
Nitric oxide (NO) induces apoptosis selectively in NADPH oxidase-1–expressing malignant cells through peroxynitrite formation after the interaction of NO with extracellular superoxide anions. Membrane-associated proton pumps ensure the protonation of peroxynitrite, followed by decomposition into NO2 and hydroxyl radicals that cause lipid peroxidation and thus trigger the mitochondrial pathway of apoptosis. Distant from the cell membrane, NO is oxidized by oxygen, whereas peroxynitrite preferentially reacts with CO2. These consumption reactions attenuate apoptosis-inducing NO/peroxynitrite signaling. There is mutual interference between NO/peroxynitrite and HOCl signaling, based on complex NO/H2O2 interactions. Tumor progression leads to resistance of tumor cells against NO/peroxynitrite-dependent signaling through expression of membrane-associated catalase that oxidizes NO and decomposes peroxynitrite. There is a fine-tuned balance between catalase-mediated oxidation of NO and NO-dependent inhibition of catalase. Increasing the NO concentration through enhancement of NOS activity or inhibition of NO dioxygenase causes local inhibition of catalase. Then the interaction between free peroxynitrite and H2O2 allows the generation of singlet oxygen, which inactivates additional catalase molecules, allowing for the generation of additional singlet oxygen. Alternatively, singlet oxygen may activate the FAS receptor and thus cause enhancement of NOX1 activity and NOS expression. This leads to an autoamplificatory enhancement of catalase inactivation, followed by intercellular ROS/RNS-mediated apoptosis-inducing signaling. In addition, the signaling molecules HOCl and peroxynitrite seem to trigger immunogenic cell death and thus might establish a beneficial cytotoxic T cell response.
IAPs: Mediators of Oncogenesis and Targets for Anticancer Therapy
399-411
10.1615/CritRevOncog.2017021084
Sarra
Bouaouiche
École Pratique des Hautes Études (EPHE), PSL Research University, Paris, France; Laboratoire d'Immunologie et Immunothérapie des Cancers (LIIC), Université de Bourgogne Franche-Comté, Dijon, France
Laurence
Dubrez
Université de Bourgogne Franche-Comté, LNC UMR1231, Dijon, France; Institut National de la Santé et de la Recherche Médicale
(Inserm), LNC UMR1231, Dijon, France
Ali
Bettaieb
École Pratique des Hautes Études (EPHE), PSL Research University, Paris, France; Laboratoire d'Immunologie et Immunothérapie des Cancers (LIIC), Université de Bourgogne Franche-Comté, Dijon, France
Stéphanie
Plenchette
École Pratique des Hautes Études (EPHE), PSL Research University, Paris, France; Laboratoire d'Immunologie et Immunothérapie des Cancers (LIIC), Université de Bourgogne Franche-Comté, Dijon, France
IAPs
oncogenesis
NF-kB
nitric oxide
The inhibitor of apoptosis (IAP) family members are potent regulators of cell homeostasis able to regulate several fundamental cellular processes that include cell death, cell proliferation, cell differentiation, and inflammation. Regarding this broad spectrum of activity, it is now becoming clear that some members of the family possess oncogenic properties. Analysis of genomic database from tumor sequencing studies has revealed a number of genetic alterations affecting some IAP genes and resulting in gain or loss of function. In this review, we discuss the
importance of IAP alterations in cell transformation and their link with key oncogenic pathways, focusing on nuclear
factor-kappa B (NF-κB)–activating signaling pathways. Then we highlight the therapeutic potential of IAP antagonists and nitric oxide (NO) donors as inhibitors of NF-κB in anticancer therapy.
Antitumoral Activity of Sorafenib in Hepatocellular Carcinoma: Effects on Cell Survival and Death Pathways, Cell Metabolism Reprogramming, and Nitrosative and Oxidative Stress
413-432
10.1615/CritRevOncog.2017021302
Francisco J.
Molina-Ruiz
Institute of Biomedicine of Seville (IBiS), IBiS/Virgen del Rocío University Hospital/CSIC/University of Seville, Seville,
Spain
Raul
Gonzalez
Institute of Biomedicine of Seville (IBiS), IBiS/Virgen del Rocío University Hospital/CSIC/University of Seville, Seville,
Spain
Maria A.
Rodriguez-Hernandez
Institute of Biomedicine of Seville (IBiS), IBiS/Virgen del Rocio University Hospital/CSIC/University of Seville, Seville,
Spain
Elena
Navarro-Villaran
Institute of Biomedicine of Seville (IBiS), IBiS/Virgen del Rocio University Hospital/CSIC/University of Seville, Seville,
Spain
Francisco J.
Padillo
Department of General Surgery, Virgen del Rocio University Hospital/IBiS/CSIC/University of Seville, Seville,
Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
Jordi
Muntané
Department of Medical Physiology and Biophysics, Laboratory 209, Institute of Biomedicine of Seville (IBiS), Av. Manuel Siurot s/n,
41013 Seville, Spain
sorafenib
hepatocellular carcinoma
antitumoral activity
autophagy
nitrosative stress
Sorafenib is an oral multikinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). Its antitumor activity is attributed to inhibition of tyrosine kinase receptors (VEGFR, PDGFR, c-kit) and intracellular
serine/threonine kinases (Raf), which alter gene expression to promote apoptosis and downregulate survival and angiogenesis pathways. The beneficial properties of sorafenib have also been related to a reduction in liver fibrosis trough regulation of TGF-βR-related STAT3 signaling. Sorafenib plays a role in the regulation of mitochondrial function, ATP, and autophagy, a process leading to either survival or apoptotic cell death depending on its intensity and duration, by altering several cellular pathways such as mTOR, AMPK, activating endoplasmic reticulum stress responses, and deregulating miRNAs that modulate autophagy. Sorafenib reduces S-nitrosation of cell death receptors and caspase-3, triggering a switch to caspase-3 from caspase-8. In this paper, we review the antitumor effects of sorafenib by interaction with cell survival and apoptosis pathways, metabolic reprogramming, and effect on oxidative and nitrosative stress, along with different mechanisms that might be involved in resistance to the drug.
Tumor Suppressor Roles of the Denitrosylase GSNOR
433-445
10.1615/CritRevOncog.2017021074
Salvatore
Rizza
Redox Signaling and Oxidative Stress Research Group, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
Giuseppe
Filomeni
Redox Signaling and Oxidative Stress Research Group, Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Biology, University of Rome Tor Vergata, Rome, Italy
GSNOR
S-nitrosylation
DNA repair
cancer metabolism
tumor suppressor
TRAP1
AGT
SDH
Nitric oxide (NO) is a gaseous pleiotropic molecule that can both induce irreversible oxidative damages and modulate physiological signal transductions by transient protein modifications, the most important of which is the
S-nitrosylation of cysteine residues. Being noxious and healthy, the role of NO in cancer is seemingly contradictory, as at low concentrations it mediates tumor growth and proliferation whereas at high concentrations it promotes apoptosis and cancer growth inhibition. However, it is becoming evident that when endogenously produced, such as upon inducible nitric oxide synthase (NOS) activation, NO acts to sustain tumorigenesis. Similarly, although less explored, defects and deficiency in the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) have been associated with the development and malignancy of liver and breast cancers, suggesting a primary role for NO signaling−that is, S-nitrosylation, being deeply involved in neoplastic transformation and progression. In this review, we summarize past and recent evidence on the role of S-nitrosylation and GSNOR in different processes that contribute to cell transformation when deregulated, such as DNA damage repair, energetic metabolism, and cell death. We also outline possible S-nitrosylation–targeted proteins that might contribute to tumorigenesis, and, finally, we speculate on the role of GSNOR in regulating the oncogenic effects induced downstream.
Therapeutic Potential of Nitric Oxide Donors in Cancer: Focus on Angiogenesis
447-458
10.1615/CritRevOncog.2017021114
Lucia
Morbidelli
Lab of Pharmacology of Angiogenesis and Microcirculation, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
tumor growth
apoptosis
angiogenesis
NO donors
NO hybrids
A new challenge to overcoming tumor resistance to conventional treatment is represented by the development
of novel nitric oxide (NO) donors. It is now clear that while low doses of NO have proneoplastic properties,
high doses exert antitumor/antiangiogenic activities through multiple mechanisms. This review focuses on the role
of exogenous NO in cancer therapy and reports the state of the art regarding different NO-donating agents in cancer
treatment, particularly in relation to angiogenesis inhibition.
INDEX VOLUME 21, 2016
459-462
10.1615/CritRevOncog.v21.i5-6.110