madman
Super Moderator
Abstract: Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro-and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, the tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment.
Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well-characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.
1. Introduction
Nitric oxide (NO) is a molecule with a very short half-life, produced by the action of nitric oxide synthases. Since NO was first discovered as being identical to endotheliumrelaxing factor, the number of biochemical and physiological processes that undergo some form of NO signaling has continued to grow. When NO was observed to influence the development, growth, and metastasis of tumor cells, many studies emerged that were in direct conflict with one another. For many years, debate raged within the community about whether NO was tumoricidal or carcinogenic. However, as the body of scientific literature grew, the role of nitric oxide within carcinogenesis has been more clearly defined. Unfortunately for those seeking to make therapeutics, nitric oxide appears to have the capability to be both tumor-promoting and tumoricidal. NO’s bimodal effects on different cancer types is a phenomenon best termed as the Yin and Yang of NO [1–3]. Determining which effect predominates is complex and often depends upon the tissue NO exerts its effects, the concentration of NO administered, and tumor microenvironment. Nevertheless, these discoveries have led to a wide number of proposed uses for NO as an anticancer agent, either alone or in combination with other treatment modalities [4]. Here, we seek to outline the complexities of NO signaling within carcinogenesis and tumor progression at the biochemical and physiological levels. Furthermore, we also discuss the impact of NO in cancer therapy and outline its role as an emerging anticancer agent.
2. Physiology of NO
2.1. Chemical Properties of NO
2.2. Synthesis of NO
2.3. NO-Mediated Post-Translational Modifications
2.4. NO cGMP Signaling Pathway
2.5. NO and Redox Balance
3. NO and the Immune Response
3.1. NO and the Antimicrobial Response
3.2. Pro-Inflammatory Response
3.3. Anti-Inflammatory Effects
4. NO and Carcinogenesis
4.1. Carcinogenesis Overview
4.2. NO Biochemistry within the TME
4.3. NO and Angiogenesis in the TME
4.4. NO and Immune Cells within the TME
4.5. NO as a Biomarker in Carcinogenesis
5. NO in Different Cancer Types
5.1. Lung Cancer
5.2. Breast Cance
5.3. Prostate Cancer
5.4. Gastrointestinal Cancers
5.5. Other Cancers
6. NO in Anticancer Therapy
6.1. NO Donors
6.2. Phosphodiesterase-Inhibitors
Phosphodiesterases (PDEs) function as metallohydralses that catalyze the breakdown of cyclic adenosine monophosphate (cAMP) or cGMP into their inactive forms, 50 -AMP or GMP [264]. PDEs are thought to be involved with cancer progression and tumor growth because of the positive association they have with increasing tumor grade and stage as well as the decrease of cAMP and cGMP noted in many tumors [265]. Elevated PDE-5 levels have been documented in various types of human carcinomas including prostate, pancreatic, lung, colon adenocarcinoma, breast, and bladder squamous carcinoma [266]. PDE-5 inhibitors (PDE-5i) blunt the function of this critical recycling enzyme and block the breakdown of cGMP in 50 -GMP, which enhances the NO/cGMP signaling pathway [44]. Thus, PDE-5is function similarly to NO donors by enhancing the effect of NO on tissue; however, they rely on endogenous sources to maintain their effect rather than the exogenous NO provided by an NO donor [267].
PDE-5is are commonly used clinically to treat erectile dysfunction (ED); however, a wide range of PDE-is have shown anticancer activity, with many tested in clinical trials (Table 4) [265]. The primary differences between PDEs and the corresponding inhibitors that determine their functional significance are their different tissue bed distributions in addition to different regulatory feedback mechanisms and affinities for cGMP, cAMP, or both [265]. For example, thymoquinone, a natural herb with PDE-1i activity, has shown efficacy at inhibiting the growth of acute lymphoblastic lymphoma, cervical, and malignant central nervous system tumor cells, and an active clinical trial investigating the efficacy of thymoquinone to treat premalignant leukoplakia has recently been completed (CT03208790) [268–272]. Numerous other phosphodiesterase inhibitors (PDE-is) have also shown similar clinical effectiveness in preclinical studies [265]. Nevertheless, PDE-is may be limited by dose toxicity and systemic side effects unrelated to the primary tumor site. One large epidemiological study of 15,000 American men suggested that the use of PDE-5is was associated with an increased incidence of melanoma; however, a retrospective meta-analysis found that although 4 out of 7 studies showed an increased risk of melanoma development with PDE-5i use, they failed to account for major confounders, and there was no linkage between the PDE-5i use and melanoma [273,274]. Interestingly, one report also suggests that PDE-5is can prevent the progression and development of prostate cancer, although other studies have shown null and even contradictory results [44,275–277]. Furthermore, the effectiveness of PDE-is as chemotherapeutics may be linked to their ability to enhance chemotherapy. Similar to PROLI/NO, PDE-5is also demonstrated that they were able to increase the transport of doxorubicin across the blood-brain barrier in a rat brain tumor model, increasing the effectiveness of chemotherapy [278]. In another study, the addition of sildenafil, a PDE-5i, with or without roflumilast, a PDE-4i, and theophylline, a methylxanthine, to lung cancer cell lines showed increased apoptosis and growth inhibition when given alongside a platinum chemotherapeutic [279]. Importantly, the same regime was not effective when combined with docetaxel, a taxane [279]. Taxanes function by disrupting microtubule disassembly, whereas platinum agents generate DNA double-stranded breaks through ROS generation. PDE-is may amplify NO’s downstream signaling cascade and increase the production of free radicals, which may then augment the free radicals produced from a platinum agent, thus increasing the efficacy of cancer. The potential anticancer mechanisms of PDE-is are numerous, and their anticancer properties were recently reviewed by Peng et al. [265]. Nevertheless, the addition of PDE-5i as adjuvant chemotherapy sensitizing agents may work through multiple mechanisms and is not strictly limited to one class of chemotherapeutic agents. Emerging evidence suggests that the sildenafil also improved the efficacy of docetaxel at treating CRPC, which the authors hypothesized was due to improved action of docetaxel on effector pathways, namely cGMP-mediated apoptosis and ERK/JNK downregulation [280]. Although numerous preclinical studies outline the potential roles for PDE-is in anticancer therapy, clinical trials (Table 4) have only begun to show evidence of efficacy [265,281]. Large, multicenter studies are needed before widespread clinical adoption of PDE-is in anticancer regimens.
6.3. Soluble Guanylate Cyclase Activators
6.4. Immunity Activators: PD-L1, PD-1, CSF1, and CSF1R
7. Future Directions
8. Conclusions
The discovery of multiple NO-mediated pathways within cancer has unlocked a number of novel NO-based therapies. Many of these novel therapies center around the delivery of NO directly to the tumor and TME. Such localized increases in NO may reverse chemotherapeutic and radiotherapeutic resistance mediated by HIF-1α, although preclinical trials have suggested the efficacy with a number of other mechanisms. However, a primary limitation is the controlled delivery of NO directly to the tumor that tightly regulates localized NO concentration while minimizing side effects. Multiple promising studies have supported the efficacy of NO-releasing biomolecules to aid in NO delivery. Advances in biomaterials, combined with multiple clinical trials demonstrating the efficacy of NO-related therapies alongside radio-, immuno-, and chemotherapy, suggest that the future of NO as an anticancer agent has only begun.
Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well-characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer.
1. Introduction
Nitric oxide (NO) is a molecule with a very short half-life, produced by the action of nitric oxide synthases. Since NO was first discovered as being identical to endotheliumrelaxing factor, the number of biochemical and physiological processes that undergo some form of NO signaling has continued to grow. When NO was observed to influence the development, growth, and metastasis of tumor cells, many studies emerged that were in direct conflict with one another. For many years, debate raged within the community about whether NO was tumoricidal or carcinogenic. However, as the body of scientific literature grew, the role of nitric oxide within carcinogenesis has been more clearly defined. Unfortunately for those seeking to make therapeutics, nitric oxide appears to have the capability to be both tumor-promoting and tumoricidal. NO’s bimodal effects on different cancer types is a phenomenon best termed as the Yin and Yang of NO [1–3]. Determining which effect predominates is complex and often depends upon the tissue NO exerts its effects, the concentration of NO administered, and tumor microenvironment. Nevertheless, these discoveries have led to a wide number of proposed uses for NO as an anticancer agent, either alone or in combination with other treatment modalities [4]. Here, we seek to outline the complexities of NO signaling within carcinogenesis and tumor progression at the biochemical and physiological levels. Furthermore, we also discuss the impact of NO in cancer therapy and outline its role as an emerging anticancer agent.
2. Physiology of NO
2.1. Chemical Properties of NO
2.2. Synthesis of NO
2.3. NO-Mediated Post-Translational Modifications
2.4. NO cGMP Signaling Pathway
2.5. NO and Redox Balance
3. NO and the Immune Response
3.1. NO and the Antimicrobial Response
3.2. Pro-Inflammatory Response
3.3. Anti-Inflammatory Effects
4. NO and Carcinogenesis
4.1. Carcinogenesis Overview
4.2. NO Biochemistry within the TME
4.3. NO and Angiogenesis in the TME
4.4. NO and Immune Cells within the TME
4.5. NO as a Biomarker in Carcinogenesis
5. NO in Different Cancer Types
5.1. Lung Cancer
5.2. Breast Cance
5.3. Prostate Cancer
5.4. Gastrointestinal Cancers
5.5. Other Cancers
6. NO in Anticancer Therapy
6.1. NO Donors
6.2. Phosphodiesterase-Inhibitors
Phosphodiesterases (PDEs) function as metallohydralses that catalyze the breakdown of cyclic adenosine monophosphate (cAMP) or cGMP into their inactive forms, 50 -AMP or GMP [264]. PDEs are thought to be involved with cancer progression and tumor growth because of the positive association they have with increasing tumor grade and stage as well as the decrease of cAMP and cGMP noted in many tumors [265]. Elevated PDE-5 levels have been documented in various types of human carcinomas including prostate, pancreatic, lung, colon adenocarcinoma, breast, and bladder squamous carcinoma [266]. PDE-5 inhibitors (PDE-5i) blunt the function of this critical recycling enzyme and block the breakdown of cGMP in 50 -GMP, which enhances the NO/cGMP signaling pathway [44]. Thus, PDE-5is function similarly to NO donors by enhancing the effect of NO on tissue; however, they rely on endogenous sources to maintain their effect rather than the exogenous NO provided by an NO donor [267].
PDE-5is are commonly used clinically to treat erectile dysfunction (ED); however, a wide range of PDE-is have shown anticancer activity, with many tested in clinical trials (Table 4) [265]. The primary differences between PDEs and the corresponding inhibitors that determine their functional significance are their different tissue bed distributions in addition to different regulatory feedback mechanisms and affinities for cGMP, cAMP, or both [265]. For example, thymoquinone, a natural herb with PDE-1i activity, has shown efficacy at inhibiting the growth of acute lymphoblastic lymphoma, cervical, and malignant central nervous system tumor cells, and an active clinical trial investigating the efficacy of thymoquinone to treat premalignant leukoplakia has recently been completed (CT03208790) [268–272]. Numerous other phosphodiesterase inhibitors (PDE-is) have also shown similar clinical effectiveness in preclinical studies [265]. Nevertheless, PDE-is may be limited by dose toxicity and systemic side effects unrelated to the primary tumor site. One large epidemiological study of 15,000 American men suggested that the use of PDE-5is was associated with an increased incidence of melanoma; however, a retrospective meta-analysis found that although 4 out of 7 studies showed an increased risk of melanoma development with PDE-5i use, they failed to account for major confounders, and there was no linkage between the PDE-5i use and melanoma [273,274]. Interestingly, one report also suggests that PDE-5is can prevent the progression and development of prostate cancer, although other studies have shown null and even contradictory results [44,275–277]. Furthermore, the effectiveness of PDE-is as chemotherapeutics may be linked to their ability to enhance chemotherapy. Similar to PROLI/NO, PDE-5is also demonstrated that they were able to increase the transport of doxorubicin across the blood-brain barrier in a rat brain tumor model, increasing the effectiveness of chemotherapy [278]. In another study, the addition of sildenafil, a PDE-5i, with or without roflumilast, a PDE-4i, and theophylline, a methylxanthine, to lung cancer cell lines showed increased apoptosis and growth inhibition when given alongside a platinum chemotherapeutic [279]. Importantly, the same regime was not effective when combined with docetaxel, a taxane [279]. Taxanes function by disrupting microtubule disassembly, whereas platinum agents generate DNA double-stranded breaks through ROS generation. PDE-is may amplify NO’s downstream signaling cascade and increase the production of free radicals, which may then augment the free radicals produced from a platinum agent, thus increasing the efficacy of cancer. The potential anticancer mechanisms of PDE-is are numerous, and their anticancer properties were recently reviewed by Peng et al. [265]. Nevertheless, the addition of PDE-5i as adjuvant chemotherapy sensitizing agents may work through multiple mechanisms and is not strictly limited to one class of chemotherapeutic agents. Emerging evidence suggests that the sildenafil also improved the efficacy of docetaxel at treating CRPC, which the authors hypothesized was due to improved action of docetaxel on effector pathways, namely cGMP-mediated apoptosis and ERK/JNK downregulation [280]. Although numerous preclinical studies outline the potential roles for PDE-is in anticancer therapy, clinical trials (Table 4) have only begun to show evidence of efficacy [265,281]. Large, multicenter studies are needed before widespread clinical adoption of PDE-is in anticancer regimens.
6.3. Soluble Guanylate Cyclase Activators
6.4. Immunity Activators: PD-L1, PD-1, CSF1, and CSF1R
7. Future Directions
8. Conclusions
The discovery of multiple NO-mediated pathways within cancer has unlocked a number of novel NO-based therapies. Many of these novel therapies center around the delivery of NO directly to the tumor and TME. Such localized increases in NO may reverse chemotherapeutic and radiotherapeutic resistance mediated by HIF-1α, although preclinical trials have suggested the efficacy with a number of other mechanisms. However, a primary limitation is the controlled delivery of NO directly to the tumor that tightly regulates localized NO concentration while minimizing side effects. Multiple promising studies have supported the efficacy of NO-releasing biomolecules to aid in NO delivery. Advances in biomaterials, combined with multiple clinical trials demonstrating the efficacy of NO-related therapies alongside radio-, immuno-, and chemotherapy, suggest that the future of NO as an anticancer agent has only begun.
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