Nitric Oxide Synthase Inhibition Prevents Cell Proliferation in Glioblastoma

Kruglyakov, Daniel; Ojha, Shashank Kumar; Kartawy, Maryam; Tripathi, Manish Kumar; Hamoudi, Wajeha; Bazbaz, Wisam; Khaliulin, Igor; Amal, Haitham

doi:10.1007/s12031-023-02166-3

Cited by 5 publications

(1 citation statement)

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“…This free radical is implicated in driving three key factors associated with unfavorable clinical outcomes in cancer: metastasis, resistance to chemo and radiotherapy, and immune suppression [ 8 , 37 , 38 ]. While some studies suggest positive effects of NO [ 39 , 40 , 41 ], the majority link high NOS2 expression to poor survival across a spectrum of hematological and solid tumors, including breast [ 8 ], pancreatic [ 42 ], nasopharyngeal carcinoma [ 43 ], colorectal [ 44 , 45 ], gastric [ 46 ], esophageal [ 47 ], prostate [ 48 ], melanoma [ 49 ], Hodgkin’s lymphoma [ 50 ], ovarian [ 51 ], squamous cell carcinoma [ 52 ], renal cell carcinoma [ 53 ], glioma [ 54 ], chondrosarcomas [ 55 ], Barrett’s esophageal adenocarcinoma [ 56 ], and in HCV-infected liver cancer patients [ 57 ].…”

Section: No In Different Cancer Typesmentioning

confidence: 99%

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

Coutinho,

Femino,

Gonzalez

et al. 2024

IJMS

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Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

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Section: No In Different Cancer Typesmentioning

confidence: 99%

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

Coutinho,

Femino,

Gonzalez

et al. 2024

IJMS

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The Role of Thioredoxin System in Shank3 Mouse Model of Autism

Bazbaz,

Kartawy,

Hamoudi

et al. 2024

J Mol Neurosci

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties in social interaction and communication, repetitive behaviors, and restricted interests. Unfortunately, the underlying molecular mechanism behind ASD remains unknown. It has been reported that oxidative and nitrosative stress are strongly linked to ASD. We have recently found that nitric oxide (NO•) and its products play an important role in this disorder. One of the key proteins associated with NO• is thioredoxin (Trx). We hypothesize that the Trx system is altered in the Shank3 KO mouse model of autism, which may lead to a decreased activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in oxidative stress, and thus, contributing to ASD-related phenotypes. To test this hypothesis, we conducted in vivo behavioral studies and used primary cortical neurons derived from the Shank3 KO mice and human SH-SY5Y cells with SHANK3 mutation. We showed significant changes in the levels and activity of Trx redox proteins in the Shank3 KO mice. A Trx1 inhibitor PX-12 decreased Trx1 and Nrf2 expression in wild-type mice, causing abnormal alterations in the levels of synaptic proteins and neurotransmission markers, and an elevation of nitrosative stress. Trx inhibition resulted in an ASD-like behavioral phenotype, similar to that of Shank3 KO mice. Taken together, our findings confirm the strong link between the Trx system and ASD pathology, including the increased oxidative/nitrosative stress, and synaptic and behavioral deficits. The results of this study may pave the way for identifying novel drug targets for ASD.

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