scholarly journals Anticancer Effect of in Vivo Inhibition of Nitric Oxide Synthase in a Rat Model of Breast Cancer

2021 ◽  
Author(s):  
Nikolay Avtandilyan ◽  
Hayarpi Javrushyan ◽  
Mikayel Ginovyan ◽  
Anna Karapetyan ◽  
Armen Trchounian
Keyword(s):  
Breast Cancer ◽  
Nitric Oxide ◽  
Cancer Treatment ◽  
No Synthase ◽  
Antitumor Effects ◽  
Blood Concentrations ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Synthase Inhibitor

Abstract High expression of nitric oxide (NO)-synthase has been found in different cancers like cervical, breast, and central nervous system. NO-synthase activity inhibition has been suggested as a possible tool to prevent breast cancer. The anti-tumor therapeutic effect of L-nitro arginine methyl ester (L-NAME) in vivo remains understudied. Here we hypothesized that NOS inhibition by L-NAME has some antitumor effects on breast cancer development as it inhibits NO levels, which is a pathophysiological modulator of cell proliferation, cell cycle arrest, apoptosis, and angiogenesis. We utilized a novel anti-cancer treatment model by the administration of NO-synthase inhibitor L-NAME (30 mg/kg in a day, intraperitoneal), injected every third day for five weeks (in parallel to tumors evolution) in opposition to high activity of NOS during 7,12-dimethylbenz[a]anthracene-induced breast tumor in rats in vivo. The blood concentrations of nitrite anions, polyamines, malondialdehyde, NH4+ levels, and arginase activity decreased in DMBA+L-NAME-treated rats compared with DMBA rats. The reduction of these compounds also affects the decrease of the mortality rate of rats, tumor number, weight and volume, and the histopathological grade of breast cancer. Treatment with L-NAME showed increases in time of tumor incidence and body weight compared with DMBA-cancer rats. Therefore, the co-administration of L-NAME influences as a potent anti-cancer agent to treat breast cancer and can lead to the development of therapeutic methods for cancers in the future.

scholarly journals Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jingjing Yang ◽  
Yulu Zhou ◽  
Shuduo Xie ◽  
Ji Wang ◽  
Zhaoqing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Morphological Changes ◽  
Tumor Model ◽  
Independent Manner ◽  
Regulated Cell Death ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Approved Drugs

Abstract Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc− inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

scholarly journals Delivery of melittin-loaded niosomes for breast cancer treatment: an in vitro and in vivo evaluation of anti-cancer effect

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Farnaz Dabbagh Moghaddam ◽  
Iman Akbarzadeh ◽  
Ehsan Marzbankia ◽  
Mahsa Farid ◽  
Leila khaledi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cell Lines ◽  
Encapsulation Efficiency ◽  
Inbred Mice ◽  
Breast Cancer Treatment ◽  
Anticancer Effect ◽  
Anti Cancer

Abstract Background Melittin, a peptide component of honey bee venom, is an appealing candidate for cancer therapy. In the current study, melittin, melittin-loaded niosome, and empty niosome had been optimized and the anticancer effect assessed in vitro on 4T1 and SKBR3 breast cell lines and in vivo on BALB/C inbred mice. "Thin-layer hydration method" was used for preparing the niosomes; different niosomal formulations of melittin were prepared and characterized in terms of morphology, size, polydispersity index, encapsulation efficiency, release kinetics, and stability. A niosome was formulated and loaded with melittin as a promising drug carrier system for chemotherapy of the breast cancer cells. Hemolysis, apoptosis, cell cytotoxicity, invasion and migration of selected concentrations of melittin, and melittin-loaded niosome were evaluated on 4T1 and SKBR3 cells using hemolytic activity assay, flow cytometry, MTT assay, soft agar colony assay, and wound healing assay. Real-time PCR was used to determine the gene expression. 40 BALB/c inbred mice were used; then, the histopathology, P53 immunohistochemical assay and estimate of renal and liver enzyme activity for all groups had been done. Results This study showed melittin-loaded niosome is an excellent substitute in breast cancer treatment due to enhanced targeting, encapsulation efficiency, PDI, and release rate and shows a high anticancer effect on cell lines. The melittin-loaded niosome affects the genes expression by studied cells were higher than other samples; down-regulates the expression of Bcl2, MMP2, and MMP9 genes while they up-regulate the expression of Bax, Caspase3 and Caspase9 genes. They have also enhanced the apoptosis rate and inhibited cell migration, invasion in both cell lines compared to the melittin samples. Results of histopathology showed reduce mitosis index, invasion and pleomorphism in melittin-loaded niosome. Renal and hepatic biomarker activity did not significantly differ in melittin-loaded niosome and melittin compared to healthy control. In immunohistochemistry, P53 expression did not show a significant change in all groups. Conclusions Our study successfully declares that melittin-loaded niosome had more anti-cancer effects than free melittin. This project has demonstrated that niosomes are suitable vesicle carriers for melittin, compare to the free form.

scholarly journals Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer

Medicines ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. 17 ◽  
Author(s):  
Maryam Nakhjavani ◽  
Jennifer E Hardingham ◽  
Helen M Palethorpe ◽  
Yoko Tomita ◽  
Eric Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Metastatic Breast ◽  
Therapeutic Agents ◽  
Ginsenoside Rg3 ◽  
Cancer Models ◽  
Anti Cancer ◽  
Ginseng Plant

Breast cancer is still one of the most prevalent cancers and a leading cause of cancer death worldwide. The key challenge with cancer treatment is the choice of the best therapeutic agents with the least possible toxicities on the patient. Recently, attention has been drawn to herbal compounds, in particular ginsenosides, extracted from the root of the Ginseng plant. In various studies, significant anti-cancer properties of ginsenosides have been reported in different cancers. The mode of action of ginsenoside Rg3 (Rg3) in in vitro and in vivo breast cancer models and its value as an anti-cancer treatment for breast cancer will be reviewed.

scholarly journals Nitric oxide inhibits basolateral 10-pS Cl− channels through the cGMP/PKG signaling pathway in the thick ascending limb of C57BL/6 mice

2016 ◽  
Vol 310 (8) ◽  
pp. F755-F762 ◽  
Author(s):  
Peng Wu ◽  
Zhongxiuzi Gao ◽  
Shiwei Ye ◽  
Zhi Qi
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylyl Cyclase ◽  
Inhibitory Effect ◽  
No Synthase ◽  
Thick Ascending Limb ◽  
Channel Activity ◽  
No Donor ◽  
Cgmp Analog ◽  
Synthase Inhibitor

We used patch-clamp techniques to examine whether nitric oxide (NO) decreases NaCl reabsorption by suppressing basolateral 10-pS Cl− channels in the thick ascending limb (TAL). Both the NO synthase substrate l-arginine (l-Arg) and the NO donor S-nitroso- N-acetylpenicillamine significantly inhibited 10-pS Cl− channel activity in the TAL. The inhibitory effect of l-Arg on Cl− channels was completely abolished in the presence of the NO synthase inhibitor or NO scavenger. Moreover, inhibition of soluble guanylyl cyclase abrogated the effect of l-Arg on Cl− channels, whereas the cGMP analog 8-bromo-cGMP (8-BrcGMP) mimicked the effect of l-Arg and significantly decreased 10-pS Cl− channel activity, indicating that NO inhibits basolateral Cl− channels by increasing cGMP production. Furthermore, treatment of the TAL with a PKG inhibitor blocked the effect of l-Arg and 8-BrcGMP on Cl− channels, respectively. In contrast, a phosphodiesterase 2 inhibitor had no significant effect on l-Arg or 8-BrcGMP-induced inhibition of Cl− channels. Therefore, we conclude that NO decreases basolateral 10-pS Cl− channel activity through a cGMP-dependent PKG pathway, which may contribute to the natriuretic and diuretic effects of NO in vivo.

Long-Term Effect of Nitric Oxide Inhibition on NA Transporter Abundance in Kidney: A Targeted Proteomics Approach.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 681-681
Author(s):  
Patricia L Turner ◽  
Shyama M E Masilamani ◽  
Ivan Reyes ◽  
Mark A Knepper
Keyword(s):  
Nitric Oxide ◽  
Polyclonal Antibodies ◽  
No Synthase ◽  
Targeted Proteomics ◽  
Long Term Effects ◽  
Long Term Effect ◽  
Proteomics Approach ◽  
Synthase Inhibitor

21 Short term effects of nitric oxide (NO) on renal Na transport are well described, but long-term effects have not been investigated. To assess the role of NO on long-term regulation of Na transporter abundance along the renal tubule, we have applied a “targeted proteomics” approach. This approach uses an array of peptide-directed polyclonal antibodies to each of the major apical Na transporters and aquaporins to assess renal abundance changes in response to a given in vivo stimulus. Rats (n=6) were treated for 3 days with 30mg/kg N G -nitro-L-arginine (L-NAME), a non-selective NO synthase inhibitor, via osmotic mini-pump, while controls (n=6) received vehicle infusion. Readout was via semiquantitative immunoblotting. The table indicates the percent changes in band density in whole kidney samples for each protein target. Similar results were seen in cortical samples from the same rats, and in additional rats with identical treatment. We conclude that long-term inhibition of NO synthase with L-NAME results in a selective increase in the abundance of NCC, the thiazide-sensitive Na-Cl transporter of the distal convoluted tubule.

scholarly journals The Application of Citrus folium in Breast Cancer and the Mechanism of Its Main Component Nobiletin: A Systematic Review

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Yuan Wu ◽  
Chien-shan Cheng ◽  
Qiong Li ◽  
Jing-xian Chen ◽  
Ling-ling Lv ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chinese Medicine ◽  
Cancer Treatment ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Drug Candidate ◽  
Antitumor Effects ◽  
Chemotherapy Drugs ◽  
Anticancer Effects

Citrus folium and its main ingredient nobiletin (NOB) have received widespread attention in recent years due to their antitumor effects. The antitumor effect of Citrus folium is related to the traditional use, mainly in its Chinese medicinal properties of soothing the liver and promoting qi, resolving phlegm, and dispelling stagnation. Some studies have proved that Citrus folium and NOB are more effective for triple-negative breast cancer (TNBC), which is related to the syndrome of stagnation of liver qi. From the perspective of modern biomedical research, NOB has anticancer effects. Its potential molecular mechanisms include inhibition of the cell cycle, induction of apoptosis, and inhibition of angiogenesis, invasion, and migration. Citrus folium and NOB can also reduce the side effects of chemotherapy drugs and reverse multidrug resistance (MDR). However, more research studies are needed to clarify the underlying mechanisms. The modern evidence of Citrus folium and NOB in breast cancer treatment has a strong connection with the traditional concepts and laws of applying Citrus folium in Chinese medicine (CM). As a low-toxic anticancer drug candidate, NOB and its structural changes, Citrus folium, and compound prescriptions will attract scientists to use advanced technologies such as genomics, proteomics, and metabolomics to study its potential anticancer effects and mechanisms. On the contrary, there are relatively few studies on the anticancer effects of Citrus folium and NOB in vivo. The clinical application of Citrus folium and NOB as new cancer treatment drugs requires in vivo verification and further anticancer mechanism research. This review aims to provide reference for the treatment of breast cancer by Chinese medicine.

scholarly journals The Involvement of Arginase and Nitric Oxide Synthase in Breast Cancer Development: Arginase and NO Synthase as Therapeutic Targets in Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Nikolay Avtandilyan ◽  
Hayarpi Javrushyan ◽  
Gayane Petrosyan ◽  
Armen Trchounian
Keyword(s):  
Breast Cancer ◽  
Nitric Oxide ◽  
Human Serum ◽  
No Synthase ◽  
Cancer Development ◽  
Cancer Cell Proliferation ◽  
Antitumor Effects ◽  
Before And After ◽  
Oxide Synthase ◽  
Burk Plot

It is well established that, during development of malignancies, metabolic changes occur, including alterations of enzyme activities and isoenzyme expression. Arginase and nitric oxide (NO) synthase (NOS) are two of those enzymes considered to be involved in tumorigenesis. The goal of this article was to study the involvement of arginase and NOS in the development of different stages of breast cancer. Our results have shown that human serum arginase activity and NO (resp., and NOS activity) and polyamines quantities increased in parallel with cancer stage progression and decreased after neoadjuvant chemotherapy. For breast cancer, the only isoenzyme of arginase expressed in serum before and after chemotherapy was in a cationic form. The data of Lineweaver-Burk plot with aKmvalue of 2 mM was calculated, which is characteristic for human liver type isoform of arginase. During electrophoresis at pH 8.9, the enzyme exhibited high electrophoretic mobility and was detected near the anode. The presented results demonstrated that arginase in human serum with breast cancer and after chemotherapy is not polymorphic. We suggest that arginase and NOS inhibition has antitumor effects on cancer development, as it can inhibit polyamines and NO levels, a precursor of cancer cell proliferation, metastasis, and tumor angiogenesis.

scholarly journals Inhibition of Respiration by Nitric Oxide Induces a Mycobacterium tuberculosis Dormancy Program

2003 ◽  
Vol 198 (5) ◽  
pp. 705-713 ◽  
Author(s):  
Martin I. Voskuil ◽  
Dirk Schnappinger ◽  
Kevin C. Visconti ◽  
Maria I. Harrell ◽  
Gregory M. Dolganov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis ◽  
No Synthase ◽  
No Production ◽  
Respiratory Pathway ◽  
Latently Infected ◽  
Synthase Inhibitor

An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.

Nitric oxide release is present from incubated skeletal muscle preparations

1994 ◽  
Vol 77 (6) ◽  
pp. 2519-2521 ◽  
Author(s):  
T. W. Balon ◽  
J. L. Nadler
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Detection System ◽  
No Synthase ◽  
Nitric Oxide Release ◽  
Metabolic Role ◽  
Longus Muscle ◽  
The Media ◽  
Synthase Inhibitor

To determine whether nitric oxide (NO) synthase activity exists in rat skeletal muscle, media from incubated rat extensor digitorum longus muscle preparations were assayed for NO with a chemiluminescent detection system. Although small amounts of NO were detected in media alone, the addition of muscle increased NO concentration in the media by 30-fold. The release of NO into the media diminished over time. Either arginine (10(-6) M), sodium nitroprusside (10(-6) M), or prior electrical stimulation in vivo caused 50–200% increases (P < 0.05) in NO concentration. NG-monomethyl-L-arginine monoacetate (10(-6) M), an NO synthase inhibitor, decreased both basal 2-deoxyglucose transport and NO efflux, indicating that NO may play a role in modulating skeletal muscle carbohydrate metabolism. These data indicate that NO is released from an incubated skeletal muscle preparation and presents the possibility that muscle-derived NO may play an important metabolic role.

Cerebellar nitric oxide is necessary for vestibulo-ocular reflex adaptation, a sensorimotor model of learning

1995 ◽  
Vol 74 (1) ◽  
pp. 489-494 ◽  
Author(s):  
J. Li ◽  
S. S. Smith ◽  
J. G. McElligott
Keyword(s):  
Nitric Oxide ◽  
Concomitant Administration ◽  
Inhibitory Effect ◽  
No Synthase ◽  
No Production ◽  
Cellular Mechanisms ◽  
Ocular Reflex ◽  
Vestibulo Ocular Reflex ◽  
Synthase Inhibitor

1. Nitric oxide (NO) production in the nervous system has been implicated in cellular mechanisms of learning and memory. Our study investigates an in vivo sensorimotor model of learning. It demonstrates that a localized vestibulocerebellar injection of the NO synthase inhibitor, L-NG-monomethyl-arginine (L-NMMA), which specifically blocks NO production, inhibited the acquisition of adaptive vestibulo-ocular reflex (VOR) gain increases but not gain decreases in the goldfish. 2. Restoration of NO production by concomitant administration of L-arginine (the substrate for NO synthase) and L-NMMA suppressed the inhibitory effect of L-NMMA on adaptive gain increases. 3. This effect of L-NMMA was stereospecific because injection of D-NMMA did not suppress adaptive VOR gain increases. 4. Injection of L-NMMA after VOR adaptation had no effect on retention, failing to alter the postadaptive recovery after a VOR gain increase. 5. In conclusion, acquisition of adaptive VOR gain increases are affected by cerebellar NO inhibition. However, because gain decreases are not, they may involve either non-NO cerebellar or extracerebellar mechanisms. In addition, different processes for acquisition and retention of gain increases may be operating, because inhibition of cerebellar NO affects the acquisition but not the retention phase.

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