Impact of the redox-active MnTnHex-2-PyP and cisplatin on the metabolome of non-small cell lung cancer cells.

Redox-based cancer therapeutic strategies aim to raise reactive oxygen species (ROS) levels in cancer cells, thus modifying their redox status, and eventually inducing cell death. Promising compounds, known as superoxide dismutase mimics (SODm), e.g.

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

Objective: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells.

Effect of the nature of the chelated metal on the photodynamic activity of metalloporphyrins.

Coordination of metal ions by the tetrapyrrolic macrocyclic ring of porphyrin-based photosensitizers (PSs) affects their photophysical properties and consequently, their photodynamic activity. Diamagnetic metals increase the singlet oxygen quantum yield while paramagnetic metals have the opposite effect. Since singlet oxygen is considered the main cell-damaging species in photodynamic therapy (PDT), the nature of the chelated cation would directly affect PDT efficacy.

Intracarotid Infusion of Redox-Active Manganese Porphyrin, MnTnBuOE-2-PyP, following Reperfusion Improves Long-Term, 28-Day Post-Stroke Outcomes in Rats.

Endovascular mechanical thrombectomy, combined with a tissue plasminogen activator (t-PA), is efficacious as a standard care for qualifying ischemic stroke patients. However, > 50% of thrombectomy patients still have poor outcomes. Manganese porphyrins, commonly known as mimics of superoxide dismutases, are potent redox-active catalytic compounds that decrease oxidative/nitrosative stress and in turn decrease inflammatory responses, mitigating therefore the secondary injury of the ischemic brain.

The Redox-Active Manganese(III) Porphyrin, MnTnBuOE-2-PyP, Impairs the Migration and Invasion of Non-Small Cell Lung Cancer Cells, Either Alone or Combined with Cisplatin.

Manganese(III) porphyrin MnTnBuOE-2-PyP (MnBuOE, BMX-001) is a third-generation redox-active cationic substituted pyridylporphyrin-based drug with a good safety/toxicity profile that has been studied in several types of cancer. It is currently in four phase I/II clinical trials on patients suffering from glioma, head and neck cancer, anal squamous cell carcinoma and multiple brain metastases. There is yet an insufficient understanding of the impact of MnBuOE on lung cancer.

Mn(III) Porphyrin, MnTnBuOE-2-PyP, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress.

Myocardial ischemia-reperfusion injury (I/R) causes damage to cardiomyocytes through oxidative stress and apoptosis. We investigated the cardioprotective effects of MnTnBuOE-2-PyP (BMX-001), a superoxide dismutase mimic, in an in vitro model of I/R injury in H9c2 cardiomyocytes. We found that BMX-001 protected against hypoxia/reoxygenation (H/R)-induced oxidative stress, as evident by a significant reduction in intracellular and mitochondrial superoxide levels.

MnTnHex-2-PyP Displays Anticancer Properties and Enhances Cisplatin Effects in Non-Small Cell Lung Cancer Cells.

The manganese(III) porphyrin MnTnHex-2-PyP (MnTnHex) is a potent superoxide dismutase mimic and modulator of redox-based transcriptional activity that has been studied in the context of different human disease models, including cancer. Nevertheless, for lung cancer, hardly any information is available. Thus, the present work aims to fill this gap and reports the effects of MnTnHex in non-small cell lung cancer (NSCLC) cells, more specifically, A549 and H1975 cells, in vitro.

Manganese Porphyrin Promotes Post Cardiac Arrest Recovery in Mice and Rats.

Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP5+, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA.

A Redox-active Mn Porphyrin, MnTnBuOE-2-PyP, Synergizes with Carboplatin in Treatment of Chemoresistant Ovarian Cell Line.

We have employed a redox-active MnP (MnTnBuOE-2-PyP, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (HO) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90).

Rotenone-Induced 4-HNE Aggresome Formation and Degradation in HL-1 Cardiomyocytes: Role of Autophagy Flux.

Reactive oxygen species (ROS) cause oxidative stress by generating reactive aldehydes known as 4-hydroxynonenal (4-HNE). 4-HNE modifies protein via covalent adduction; however, little is known about the degradation mechanism of 4-HNE-adducted proteins. Autophagy is a dynamic process that maintains cellular homeostasis by removing damaged organelles and proteins.

MnTnHex-2-PyP, Coupled to Radiation, Suppresses Metastasis of 4T1 and MDA-MB-231 Breast Cancer via AKT/Snail/EMT Pathways.

Tumor migration and invasion induced by the epithelial-to-mesenchymal transition (EMT) are prerequisites for metastasis. Here, we investigated the inhibitory effect of a mimic of superoxide dismutase (SOD), cationic Mn(III) -substituted -n-hexylpyridylporphyrin (MnTnHex-2-PyP, MnHex) on the metastasis of breast cancer in cellular and animal models, focusing on the migration of tumor cells and the factors that modulate this behavior. Wound healing and Transwell migration assays revealed that the migration of mouse mammary carcinoma 4T1 cells was markedly reduced during the concurrent treatment of MnHex and radiation therapy (RT) compared with that of the control and RT alone.

Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins-Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions.

High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three isomeric Mn(III) substituted -alkyl- and alkoxyalkylpyridylporphyrins or isomeric Mn(III) -methylpyridyl analog, commonly known as mimics of superoxide dismutase.

Ascorbate-dependent and ascorbate-independent Mn porphyrin cytotoxicity: anticancer activity of Mn porphyrin-based SOD mimics through ascorbate-dependent and -independent routes.

Objective: The aim of this study was to investigate how modifications at the periphery of the porphyrin ring affect the anticancer activity of Mn porphyrins (MnPs)-based SOD mimics.

Methods: Six compounds: MnTE-2-PyP with a short ethyl chain on the pyridyl ring; MnTnHexOE-2-PyP and MnTnOct-2-PyP with linear 8-atom alkyl chains, but the former with an oxygen atom within the alkyl chain; MnTE-2-PyPhP and MnTPhE-2-PyP with pyridyl and phenyl substituents, were investigated. Cytotoxicity was studied using pII and MDA-MB-231 cancer cell lines.

HO-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways.

Mn(III) --alkyl- and -alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO, HO, HS, CO , ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells.

Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models.

Oxidative stress that results from an imbalance between the concentrations of reactive species (RS) and antioxidant defenses is associated with many pathologies. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase are among the key enzymes that maintain the low nanomolar physiological concentrations of superoxide and hydrogen peroxide. The increase in the levels of these species and their progeny could have deleterious effects.

Antibacterial Activity of Synthetic Cationic Iron Porphyrins.

Widespread antibiotic resistance demands new strategies for fighting infections. Porphyrin-based compounds were long ago introduced as photosensitizers for photodynamic therapy, but light-independent antimicrobial activity of such compounds has not been systematically explored. The results of this study demonstrate that synthetic cationic amphiphilic iron -alkylpyridylporphyrins exert strong bactericidal action at concentrations as low as 5 μM.

Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (HO)MnTnHex-2-PyP.

Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (HO)MnTnHex-2-PyP (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood-brain barrier, and improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion (MCAO) ischemic stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited by an adverse effect of arterial hypotension.

Mn porphyrins as a novel treatment targeting sickle cell NOXs to reverse and prevent acute vaso-occlusion in vivo.

In sickle cell disease (SCD), adhesion of sickle red blood cells (SSRBCs) and activated leukocytes in inflamed venules affects blood rheology, causing vaso-occlusive manifestations and vital reduction in microvascular blood flow. Recently, we found that NADPH oxidases (NOXs) create a vicious feedback loop within SSRBCs. This positive feedback loop mediates SSRBC adhesion to the endothelium.

Redox-Active Drug, MnTE-2-PyP, Prevents and Treats Cardiac Arrhythmias Preserving Heart Contractile Function.

Background: Cardiomyopathies remain among the leading causes of death worldwide, despite all efforts and important advances in the development of cardiovascular therapeutics, demonstrating the need for new solutions. Herein, we describe the effects of the redox-active therapeutic Mn(III) -tetrakis(-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP), on rat heart as an entry to new strategies to circumvent cardiomyopathies.

Methods: Wistar rats weighing 250-300 g were used in both and experiments, to analyze intracellular Ca dynamics, L-type Ca currents, Ca spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP-treated cells, hearts, or animals.

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism.

Manganese porphyrins (MnPs), MnTE-2-PyP, MnTnHex-2-PyP and MnTnBuOE-2-PyP, are superoxide dismutase (SOD) mimetics and form a redox cycle between O and reductants, including ascorbic acid, ultimately producing hydrogen peroxide (HO). We previously found that MnPs oxidize hydrogen sulfide (HS) to polysulfides (PS; HS, n = 2-6) in buffer. Here, we examine the effects of MnPs for 24 h on HS metabolism and PS production in HEK293, A549, HT29 and bone marrow derived stem cells (BMDSC) using HS (AzMC, MeRho-AZ) and PS (SSP4) fluorophores.

Manganese Porphyrin-Based SOD Mimetics Produce Polysulfides from Hydrogen Sulfide.

Manganese-centered porphyrins (MnPs), MnTE-2-PyP (MnTE), MnTnHex-2-PyP (MnTnHex), and MnTnBuOE-2-PyP (MnTnBuOE) have received considerable attention because of their ability to serve as superoxide dismutase (SOD) mimetics thereby producing hydrogen peroxide (HO), and oxidants of ascorbate and simple aminothiols or protein thiols. MnTE-2-PyP and MnTnBuOE-2-PyP are now in five Phase II clinical trials warranting further exploration of their rich redox-based biology. Previously, we reported that SOD is also a sulfide oxidase catalyzing the oxidation of hydrogen sulfide (HS) to hydrogen persulfide (HS) and longer-chain polysulfides (HS, = 3-7).

The SOD Mimic MnTnHex-2-PyP Reduces the Viability and Migration of 786-O Human Renal Cancer Cells.

Clear-cell renal carcinoma (ccRCC) is the most common type of renal cancer. The importance of oxidative stress in the context of this disease has been described, although there is only little information concerning the role of superoxide dismutase (SOD) enzymes. The importance of SOD in different pathological conditions promoted the development of SOD mimics (SODm).

Thiol regulation by Mn porphyrins, commonly known as SOD mimics.

Superoxide dismutases play an important role in human health and disease. Three decades of effort have gone into synthesizing SOD mimics for clinical use. The result is the Mn porphyrins which have SOD-like activity.