The Nitric Oxide Donor [Zn(PipNONO)Cl] Exhibits Antitumor Activity through Inhibition of Epithelial and Endothelial Mesenchymal Transitions

Ciccone, Valerio; Filippelli, Arianna; Bacchella, Chiara; Monzani, Enrico; Morbidelli, Lucia

doi:10.3390/cancers14174240

Cited by 7 publications

(5 citation statements)

References 73 publications

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“…One example is the inhibition of melanoma cell growth observed upon scavenging endogenous NO, which was restored by using a NO donor [10]. However, NO-induced melanoma apoptosis and its mechanism is not clearly understood.…”

Section: Discussionmentioning

confidence: 99%

Effect of dose-rate on nitric oxide-induced apoptosis in A375 human melanoma cells

Moon,

Kim

2024

Trop. J. Pharm Res

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Purpose: To investigate the effect of dose-rate on nitric oxide (NO)-induced apoptosis in A375 human melanoma cells. Methods: The A375 cells were exposed to NO at a steady-state concentration of 7 μM, similar to the level estimated to occur in vivo in inflamed tissues, and delivered by diffusion through silastic tubing. Trypan blue dye exclusion assay was used to assess cell proliferation and viability. Cell cycle was studied by propidium iodide (PI) staining while Annexin V-FITC and PI assays were used to evaluate apoptosis. Western blotting assay was carried out to determine protein levels of p53, Bax, DR4, DR5, Fas (CD95), Procaspase 8, Procaspase 9 and Procaspase 3. Results: Viability of A375 cells was reduced by 22 % after 24 h leading to extensive apoptosis and cell cycle arrest following exposure to a cumulative dose of 3360 μM/min NO. Treatment with NO stimulated p53 and triggered mitochondrial apoptotic events by inducing conformational changes in Bax. Also, activation of caspase 9 and 3, DR4, DR5, Fas (CD95) and caspase 8 appeared to be mediated concurrently by death receptor processing and downstream caspases. Conclusion: Nitric oxide (NO) induces programmed cell death, thus indicating that it could serve as an effective inhibitor to halt the progression of melanoma or as an enhancer to improve therapeutic strategies for treatment.

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Section: Discussionmentioning

confidence: 99%

Effect of dose-rate on nitric oxide-induced apoptosis in A375 human melanoma cells

Moon,

Kim

2024

Trop. J. Pharm Res

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“…Inducible NOS (iNOS) and NO downregulation promoted EMT and metastasis in colorectal cancer [ 20 ]. An NO donor exhibited antitumour activity through inhibition of EMT in human lung cancer and melanoma cells [ 21 ]. Increased reactive oxygen species (ROS) levels lead to the development of fibrosis by inducing oxidative damage during EMT in the lens.…”

Section: Discussionmentioning

confidence: 99%

“…In lens fibrosis, L-arginine metabolism is altered by the expression and activity of ARG1, which ultimately affects collagen synthesis. Exogenous NO may retard the development of fibrosis by preventing oxidative damage-induced EMT [ 20 , 21 ]. Arginase activation leads to decreased NO bioavailability, increased superoxide levels, and decreased antifibrotic effects [ 22 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

Arginase-1 promotes lens epithelial-to-mesenchymal transition in different models of anterior subcapsular cataract

Li,

Wang,

Shi

et al. 2023

Cell Commun Signal

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Background Arginase-1 (ARG1) promotes collagen synthesis and cell proliferation. ARG1 is highly expressed in various tumour cells. The mechanisms of ARG1 in epithelial-to-mesenchymal transition (EMT)-associated cataracts were studied herein. Methods C57BL/6 mice, a human lens epithelial cell line (HLEC-SRA01/04), and human lens capsule samples were used in this study. The right lens anterior capsule of the mouse eye was punctured through the central cornea with a 26-gauge hypodermic needle. Human lens epithelial cells (HLECs) were transfected with ARG1-targeted (siARG1) or negative control siRNA (siNC). For gene overexpression, HLECs were transfected with a plasmid bearing the ARG1 coding sequence or an empty vector. Medium containing 0.2% serum with or without transforming growth factor beta-2 (TGF-β2) was added for 6 or 24 h to detect mRNA or protein, respectively. The expression of related genes was measured by quantitative real-time polymerase chain reaction (RT–qPCR), western blotting, and immunohistochemical staining. Transwell assays and wound healing assays were used to determine cell migration. Cell proliferation, superoxide levels, nitric oxide (NO) levels, and arginase activity were estimated using Cell Counting Kit-8 assays, a superoxide assay kit, an NO assay kit, and an arginase activity kit. Results ARG1, alpha-smooth muscle actin (α-SMA), fibronectin, and Ki67 expression increased after lens capsular injury, while zonula occludens-1 (ZO-1) expression decreased. Fibronectin and collagen type I alpha1 chain (collagen 1A1) expression increased, and cell migration increased significantly in ARG1-overexpressing HLECs compared with those transfected with an empty vector after TGF-β2 treatment. These effects were reversed by ARG1 knockdown. The arginase-related pathway plays an important role in EMT. mRNAs of enzymes of the arginase-related pathway were highly expressed after ARG1 overexpression. ARG1 knockdown suppressed these expression changes. Numidargistat (CB-1158) dihydrochloride (CB-1158), an ARG1 inhibitor, suppressed TGF-β2-induced anterior subcapsular cataract (ASC) by reducing the proliferation of lens epithelial cells (LECs) and decreasing fibronectin, α-SMA, collagen 1A1, and vimentin expression. Compared with that in nonanterior subcapsular cataract (non-ASC) patients, the expression of ARG1, collagen 1A1, vimentin, fibronectin, and Ki67 was markedly increased in ASC patients. Conclusions ARG1 can regulate EMT in EMT-associated cataracts. Based on the pathogenesis of ASC, these findings are expected to provide new therapeutic strategies for patients. Graphical abstract

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“…Endothelial cells co-cultured with lung cancer cells were shown to acquire a mesenchymal phenotype with increased vimentin, alpha smooth muscle actin and Smad2/3, and reduced VE-cadherin. These changes were prevented in the presence of [Zn(PipNONO)Cl], suggesting [Zn(PipNONO)Cl] as a promising therapeutic tool to control tumor growth and metastasis [ 146 ]. In another study, alpha-1 antitrypsin was shown to induce EndMT in lung cancer cells, suggesting alpha-1 antitrypsin as a factor associated with tumor metastasis in lung carcinoma [ 147 ].…”

Section: Extravasation Of Tumor Cells Through the Blood–brain Barrier...mentioning

confidence: 99%

Insights into the Molecular Mechanisms Mediating Extravasation in Brain Metastasis of Breast Cancer, Melanoma, and Lung Cancer

Alsabbagh

Ahmed

Alqudah

et al. 2023

Cancers

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Brain metastasis is an incurable end-stage of systemic cancer associated with poor prognosis, and its incidence is increasing. Brain metastasis occurs through a multi-step cascade where cancer cells spread from the primary tumor site to the brain. The extravasation of tumor cells through the blood–brain barrier (BBB) is a critical step in brain metastasis. During extravasation, circulating cancer cells roll along the brain endothelium (BE), adhere to it, then induce alterations in the endothelial barrier to transmigrate through the BBB and enter the brain. Rolling and adhesion are generally mediated by selectins and adhesion molecules induced by inflammatory mediators, while alterations in the endothelial barrier are mediated by proteolytic enzymes, including matrix metalloproteinase, and the transmigration step mediated by factors, including chemokines. However, the molecular mechanisms mediating extravasation are not yet fully understood. A better understanding of these mechanisms is essential as it may serve as the basis for the development of therapeutic strategies for the prevention or treatment of brain metastases. In this review, we summarize the molecular events that occur during the extravasation of cancer cells through the blood–brain barrier in three types of cancer most likely to develop brain metastasis: breast cancer, melanoma, and lung cancer. Common molecular mechanisms driving extravasation in these different tumors are discussed.

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The Nitric Oxide Donor [Zn(PipNONO)Cl] Exhibits Antitumor Activity through Inhibition of Epithelial and Endothelial Mesenchymal Transitions

Cited by 7 publications

References 73 publications

Effect of dose-rate on nitric oxide-induced apoptosis in A375 human melanoma cells

Effect of dose-rate on nitric oxide-induced apoptosis in A375 human melanoma cells

Arginase-1 promotes lens epithelial-to-mesenchymal transition in different models of anterior subcapsular cataract

Insights into the Molecular Mechanisms Mediating Extravasation in Brain Metastasis of Breast Cancer, Melanoma, and Lung Cancer

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