Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy

Journal of Experimental Pharmacology, Journal Year: 2021, Volume and Issue: Volume 13, P. 303 - 328

Published: March 1, 2021

Abstract: Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head neck, lung, ovarian, testicular cancers, sarcoma. is commonly administered intravenously a first-line chemotherapy patients suffering from various malignancies. Upon absorption into cancer cell, cisplatin interacts with cellular macromolecules exerts its cytotoxic effects through series biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) forming intra-strand DNA adducts leading inhibition synthesis cell growth. Its primary molecular mechanism action has associated induction both intrinsic extrinsic pathways apoptosis resulting production reactive oxygen species lipid peroxidation, activation signal transduction pathways, p53 signaling cycle arrest, upregulation pro-apoptotic genes/proteins, down-regulation proto-oncogenes anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies reported substantial side monotherapy, while others shown drug resistance in some patients. Hence, new formulations several combinational therapies tested purpose improving utility cisplatin. Therefore, this review provides comprehensive understanding therapy discusses therapeutic approaches overcome effects. Keywords: cisplatin, action, combination therapy,

Language: Английский

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NRF2 as a regulator of cell metabolism and inflammation in cancer

Carcinogenesis, Journal Year: 2020, Volume and Issue: 41(4), P. 405 - 416

Published: April 1, 2020

Nuclear factor erythroid 2-related 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing stress tumor-promoting inflammation, many cancers exhibit elevated activity either due to mutations that disrupt the negative control or other factors. Importantly, associated with poor prognosis has turned out be key activator cancer-supportive anabolic metabolism. In this review, we summarize diverse roles played in focusing on metabolic reprogramming inflammation.

Language: Английский

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LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma

Cancer Research, Journal Year: 2019, Volume and Issue: 79(13), P. 3251 - 3267

Published: April 30, 2019

Abstract In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared KL tumors, KLK exhibited increased expression genes involved in glutamine metabolism, tricarboxylic acid cycle, redox homeostasis signature. Using isogenic pairs knockdown or overexpression LKB1, KEAP1, NRF2, found that results energetic stress marked by levels intracellular reactive oxygen species decreased ATP, NADPH/NADP+ ratio, glutathione. Activation axis LKB1-deficient cells enhanced cell survival played a critical role maintenance glutamine-dependent manner. pathways cooperatively drove metabolic reprogramming sensitivity to glutaminase inhibitor CB-839 vitro vivo. Overall, findings elucidate adaptive advantage provided activation support clinical testing subsets adenocarcinoma. Significance: non–small cancer, energetic/redox stress, is tolerated, part, through KEAP1/NRF2–dependent adaptations, thus enhancing dependence vulnerability inhibition.

Language: Английский

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Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway

Redox Biology, Journal Year: 2022, Volume and Issue: 54, P. 102389 - 102389

Published: June 29, 2022

The KEAP1-NRF2-ARE signaling pathway plays a central role in mediating the adaptive cellular stress response to oxidative and electrophilic chemicals. This canonical has been extensively studied reviewed past two decades, but rarely was it looked at from quantitative perspective. Signal amplification, i.e., ultrasensitivity, is crucially important for robust induction of antioxidant genes appropriate levels that can adequately counteract stresses. In this review article, we examined number well-known molecular events perspective with focus on how signal amplification be achieved. We illustrated, by using series mathematical models, redox-regulated protein sequestration, stabilization, translation, nuclear trafficking, DNA promoter binding, transcriptional – which are embedded network comprising KEAP1, NRF2, sMaf, p62, BACH1 may generate highly ultrasensitive NRF2 activation gene induction. emergence degree ultrasensitivity depend strengths protein-protein protein-DNA interaction abundances. A unique, understanding will help identify sensitive targets prevention therapeutics stress-related diseases develop adverse outcome models facilitate health risk assessment

Language: Английский

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Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway

Redox Biology, Journal Year: 2018, Volume and Issue: 18, P. 124 - 137

Published: July 5, 2018

Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear erythroid 2-related 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4′,5-trihydroxy-stilbene-3-β-D-glucoside), polyphenol found the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway fructose-induced inflammation lipid deposition blockade polydatin are still not clear. Here, we detected down-regulation, Keap1 up-regulation, Nrf2 antioxidant inactivation, ROS-driven thioredoxin-interacting (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation dysregulation peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging (SREBP-1) stearoyl-CoA desaturase-1 (SCD-1) rat livers, BRL-3A HepG2 cells under high fructose induction. Furthermore, data from treatment or transfection minic, TXNIP siRNA, activator ROS inhibitor demonstrated that low-expression increased block pathway, then enhanced activate NLRP3 disturb metabolism-related proteins, causing cells. We also up-regulated inhibit resulting attenuation these disturbances animal cell models. These findings provide novel pathological mechanism redox status imbalance suggest enhancement control by therapeutic strategy for fructose-associated deposition.

Language: Английский

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The Crosstalk between Nrf2 and Inflammasomes

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(2), P. 562 - 562

Published: Feb. 13, 2018

The Nrf2 (nuclear factor E2-related or nuclear (erythroid-derived 2)-like 2) transcription is a key player in cytoprotection and activated stress conditions caused by reactive oxygen species (ROS) electrophiles. Inflammasomes represent central regulators of inflammation. Upon detection various factors, assembly the inflamasome protein complex results activation secretion proinflammatory cytokines. In addition, inflammasome causes pyroptosis, lytic form cell death, which supports There growing evidence crosstalk between pathways at different levels. For example, activating compounds inhibit inflammasomes consequently This review summarizes what known about predominantly antagonistic relationship both stress-activated pathways.

Language: Английский

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Pathophysiological Aspects of Alcohol Metabolism in the Liver

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(11), P. 5717 - 5717

Published: May 27, 2021

Alcoholic liver disease (ALD) is a globally prevalent chronic caused by or binge consumption of alcohol. The the major organ that metabolizes alcohol; therefore, it particularly sensitive to alcohol intake. Metabolites and byproducts generated during metabolism cause damage, leading ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, inducing fibrosis. Despite severity ALD, development novel treatments has been hampered lack animal models fully mimic human ALD. To overcome current limitations studies therapy development, necessary understand molecular mechanisms underlying alcohol-induced injury. Hence, provide insights into progression this review examines previous conducted on in liver. There particular focus occurrence hepatotoxicity originating from metabolism.

Language: Английский

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Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid

Antioxidants, Journal Year: 2022, Volume and Issue: 11(10), P. 1993 - 1993

Published: Oct. 7, 2022

Ascorbic acid, as a one of the basic exogenous vitamins, occurs in body form ascorbate, known for its strong antioxidant and anti-inflammatory properties. The presented review shows not only importance ascorbate free radical scavenger but also summarizes action based on other mechanisms, including activation intracellular systems effect NFκB/TNFα pathway apoptosis. Ascorbate interacts with small-molecule antioxidants, tocopherol, glutathione, thioredoxin; it can stimulate biosynthesis enzymes, such superoxide dismutase, catalase, or glutathione peroxidase. Moreover, promotes activity transcription factors (Nrf2, Ref-1, AP-1), which enables expression genes encoding proteins. Additionally, supports mainly polyphenols. In this regard, both DNA, proteins, lipids are protected against oxidation, leading to an inflammatory reaction even cell death. Although has properties, have pro-oxidant effects presence transition metals. However, role prevention DNA mutation, inflammation, apoptosis, especially relation cancer cells, is controversial.

Language: Английский

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The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway

Biomedicine & Pharmacotherapy, Journal Year: 2020, Volume and Issue: 127, P. 110234 - 110234

Published: May 21, 2020

Resveratrol is a natural polyphenol derived from grapes, berries, red wine, peanuts amongst other fruits and nuts. Beneficial effects such as anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, cardioprotective, renoprotective, anti-obesity, anti-diabetic, anti-cancer of resveratrol have been demonstrated by preclinical clinical research. A possibility that these therapeutical are associated with modulation the Nrf2 signaling pathway in following way: may potentiate through blockage Keap1, means changing mediators, its expression nuclear translocation. This article reviews evidence modulating hypothesis possible molecular mechanism underlying medicinal properties resveratrol.

Language: Английский

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Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

Biomolecules, Journal Year: 2021, Volume and Issue: 11(4), P. 589 - 589

Published: April 16, 2021

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes reaction's rate-limiting step, resulting in release carbon monoxide (CO), ferrous ions, and biliverdin (BV), which successively reduced bilirubin (BR) by reductase. Several studies have drawn attention to controversial role HO-1, inducible isoform, pointing out its implications cancer other diseases development, but also underlining importance antioxidant activity. The contribution HO-1 redox homeostasis leads a relevant decrease cells oxidative damage, can be reconducted cytoprotective effects explicated alongside mechanisms involving genes like TIGAR (TP53-induced glycolysis apoptosis regulator), therapeutic functions heme main transformation products, especially has been shown effective on GSH levels implementation sustaining body's response stress. aim this review was collect most knowledge from literature, analyzing different perspectives try put forward hypothesis revealing yet unknown HO-1-involved pathways that could useful promote development new therapeutical strategies, lay foundation further investigation fully understand important system.

Language: Английский

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