Nitric oxide synthase inhibitors 1400W and L-NIO inhibit angiogenesis pathway of colorectal cancer

Gao, Yanfeng; Zhou, Shuang; Xu, Yi; Sheng, Sen; Qian, Steven Y.; Huo, Xiongwei

doi:10.1016/j.niox.2018.12.008

Cited by 31 publications

(29 citation statements)

References 36 publications

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“…Our recent study [64] confirmed that the blockage of iNOS or eNOS significantly inhibited CRC cell proliferation due to the reduced level of NO. Two NOS inhibitors, 1400 W and L-NIO, hindered the CRC cell growth and migration.…”

Section: W and L-niosupporting

confidence: 59%

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

Wang

Xie

et al. 2020

Cancers

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Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)—a free-radical gas—plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.

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Section: W and L-niosupporting

confidence: 59%

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

Wang

Xie

et al. 2020

Cancers

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“…In COAD, NOS3 expressed relatively high level in tumour tissues and cancer cell lines, and patients with higher NOS3 levels were diagnosed with a later tumour stage. This was consistent with the observation that L-NIO (a NOS3 inhibitor) inhibited cell growth and angiogenesis in colorectal cancer, and the anti-tumour effect of E7080 (lenvatinib) could be increased after combination with L-NIO in colorectal cancer (31,32). Although the analyses of NOS3 expression from the current TCGA data was not statistically relevant to the prognosis in COAD patients, Marisi et al found that the NOS3 expression level affected the progression-free survival and overall survival (OS) of metastatic colorectal cancer patients (9).…”

Section: Discussionsupporting

confidence: 90%

“…Another NOS3 inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) was also reported to inhibit PAAD tumour growth (15). In addition, L-NIO could promote the anti-tumour effect of lenvatinib (31,32). The NOS3 level was signi cantly correlated with outcomes of bevacizumab-based chemotherapy in COAD (9,35).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Expression of NOS3 and Association with Clinical Outcome are Highly Cancer Dependent as Revealed through Pan-Cancer Analysis

Zou¹,

Lv²,

Yang³

et al. 2019

Preprint

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Background: NOS3 (endothelial NOS, eNOS) is a member of the nitric oxide synthase (NOS) enzyme family, mainly participating in nitric oxide (NO) generation. NOS3 has been reported to inhibit apoptosis and promote angiogenesis, proliferation, and invasiveness. However, the expression pattern of NOS3 and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective. Methods: In this research, data from the Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Therapeutics Response Portal (CTRP) were employed and NOS3 expression was comprehensively analysed in normal tissues, cancer tissues and cell lines. Its relationship with clinical phenotypes and drug responses was also analysed. Results: In normal tissues, NOS3 was expressed at the highest levels in the spleen and the lowest levels in the blood. Compared with the corresponding normal tissues, its expression in tumour was significantly increased in seven tumour types but decreased in eight tumour types. And NOS3 expression was positively or negatively related to tumour stage and overall survival of patients depending on the tumour types. The expression of NOS3 was related to the response to ‘SR8278’. Conclusions: NOS3 was differentially expressed in tumour tissues, and had prognosis value in some tumour types. And its correlation to drug response warrants further investigation.

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“…S100B activity led to a significant increase of both VEGF and NO release from cultured cells, that paralleled a marked upregulation of VEGF receptors 1/2 and iNOS protein expression in the same experimental conditions. VEGF and NO are crucial components of the angiogenesis network since they synergistically promote a pro-angiogenic milieu in the colon [26,27]. Different evidence produced by our research group has been addressed in the attempt to clarify the role exerted by an increased S100B level and perpetuation of chronic inflammation in the gut mucosa.…”

Section: Discussionmentioning

confidence: 99%

S100B Protein Stimulates Proliferation and Angiogenic Mediators Release through RAGE/pAkt/mTOR Pathway in Human Colon Adenocarcinoma Caco-2 Cells

Seguella

Capuano

Pesce

et al. 2019

IJMS

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Chronic inflammation and angiogenesis are associated with colonic carcinogenesis. Enteric glia-derived S100B protein has been proposed as an “ideal bridge”, linking colonic inflammation and cancer, given its dual ability to up-regulate nuclear factor-kappaB (NF-κB) transcription via receptor for advanced glycation end products (RAGE) signaling and to sequestrate wild type pro-apoptotic wild type (wt)p53. However, its pro-angiogenic effects on cancer cells are still uninvestigated. To this aim, we evaluated the effect of exogenous S100B (0.05–5 µM) protein alone or in the presence of S100B blocking monoclonal antibody (mAb) (1:105–1:104 v/v diluted) on (1) cultured Caco-2 cells proliferation, migration and invasiveness in vitro, respectively by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)-formazan, wound healing and matrigel invasion assays and (2) its effect on the release of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF) by ELISA and immunofluorescence analyses. The effect of S100B alone or in the presence of S100BmAb was then investigated on RAGE/pAkt/mammalian target of rapamycin (mTOR) signaling pathway by immunoblot analysis. Our results showed that S100B markedly increases proliferation and invasiveness of Caco-2 cells, through the release of pro-angiogenic VEGF and NO paralleled to a significant decrease of wtp53 expression mediated by RAGE-p38 mitogen-activated protein kinase (MAPK)/pAkt-mTOR and hypoxia-inducible factor 1-alpha (HIF1α) pathways. Such effects were counteracted by S100BmAb, indicating that S100B targeting is a potential approach to inhibit colon carcinoma proliferation and angiogenesis.

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Nitric oxide synthase inhibitors 1400W and L-NIO inhibit angiogenesis pathway of colorectal cancer

Cited by 31 publications

References 36 publications

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

Abnormal Expression of NOS3 and Association with Clinical Outcome are Highly Cancer Dependent as Revealed through Pan-Cancer Analysis

S100B Protein Stimulates Proliferation and Angiogenic Mediators Release through RAGE/pAkt/mTOR Pathway in Human Colon Adenocarcinoma Caco-2 Cells

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