Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

Medicinal Research Reviews, Journal Year: 2018, Volume and Issue: 38(6), P. 1799 - 1836

Published: April 10, 2018

Human carbonic anhydrase (CA) IX is a tumor-associated protein, since it scarcely present in normal tissues, but highly overexpressed large number of solid tumors, where actively contributes to survival and metastatic spread tumor cells. Due these features, the characterization its biochemical, structural, functional features for drug design purposes has been extensively carried out, with consequent development several selective small molecule inhibitors monoclonal antibodies be used different purposes. Aim this review provide comprehensive state-of-the-art studies performed on enzyme, regarding functional, biomedical aspects, as well molecules diagnostic therapeutic applications cancer treatment. A brief description additional pharmacologic CA inhibition other diseases, such arthritis ischemia, also provided.

Language: Английский

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Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors

Expert Opinion on Investigational Drugs, Journal Year: 2018, Volume and Issue: 27(12), P. 963 - 970

Published: Nov. 14, 2018

Introduction: Hypoxic tumors overexpress two carbonic anhydrases (CA, EC 4.2.1.1), CA IX and XII, involved in complex processes connected to tumorigenesis (pH regulation, metabolism, invasion, dissemination of the tumor). The biochemical rationale behind these is orchestrated by transcription factor hypoxia inducible 1 (HIF-1).Areas covered: XII have been validated as antitumor/antimetastatic drug targets may be used for imaging hypoxic tumors. Many inhibitors (CAIs) belonging sulfonamide, coumarin sulfocoumarin classes selectively inhibit isoforms. IX/XII growth primary formation metastases deplete cancer stem cell population, alone or combination with other agents. These are three beneficial antitumor mechanisms that make them unique among anticancer drugs available.Expert opinion: Indisulam entered clinical trials an sulfonamide; it progressed Phase II but was terminated 2016. However, SLC-0111, a sulfonamide inhibitor 1, recently completed successful I trial treatment advanced, metastatic solid This compound now Ib/II being assessed monotherapy agents such gemcitabine. synergistic (cisplatin, proton pump inhibitors, doxorubicin, temozolamide) versatile, emerging class drugs.

Language: Английский

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Carbonic Anhydrases and Metabolism

Metabolites, Journal Year: 2018, Volume and Issue: 8(2), P. 25 - 25

Published: March 21, 2018

Although the role of carbonic anhydrases (CAs, EC 4.2.1.1) in metabolism is well-established, pharmacological applications this phenomenon started to be considered only recently. In organisms all over phylogenetic tree, seven CA genetic families known date are involved biosynthetic processes and pH modulation, which may influence multiple ways, with both being amenable pharmacologic intervention. inhibitors possess antiobesity action directly by inhibiting lipogenesis, whereas hypoxic tumor highly controlled transmembrane isoforms IX XII, contribute acidic extracellular environment tumors supply bicarbonate for their high proliferation rates. Many articles from special issue deal cancer CAs how these phenomena can used designing innovative antitumor therapies/imaging agents. The metabolic roles bacteria algae also discussed.

Language: Английский

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Carbonic anhydrase IX and acid transport in cancer

British Journal of Cancer, Journal Year: 2019, Volume and Issue: 122(2), P. 157 - 167

Published: Dec. 10, 2019

Alterations in tumour metabolism and acid/base regulation result the formation of a hostile environment, which fosters growth metastasis. Acid/base homoeostasis cancer cells is governed by concerted interplay between carbonic anhydrases (CAs) various transport proteins, either mediate proton extrusion or shuttling equivalents, such as bicarbonate lactate, across cell membrane. Accumulating evidence suggests that some these transporters interact both directly functionally with CAIX to form protein complex coined 'transport metabolon'. Transport metabolons formed require CA catalytic activity have function migration invasion. Another type metabolon monocarboxylate transporters. In this complex, functions antenna for transporter, drives export lactate protons from cell. Since almost exclusively expressed cells, might serve promising targets interfere pH energy metabolism. This review provides an overview current state research on discusses how could be exploited modern therapy.

Language: Английский

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Investigation of inhibitory properties of some hydrazone compounds on hCA I, hCA II and AChE enzymes

Bioorganic Chemistry, Journal Year: 2019, Volume and Issue: 86, P. 316 - 321

Published: Feb. 4, 2019

Language: Английский

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Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

Redox Biology, Journal Year: 2019, Volume and Issue: 26, P. 101297 - 101297

Published: Aug. 10, 2019

Hypoxia and acidity provide microenvironment for selection under evolutionary pressure proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present all life kingdoms, equilibrating the reactions among CO2, bicarbonate H+. CA9, membrane-associated α-CA, has been drug target various cancers. Whereas iron is essential not only cells but also lives on earth, little known association hypoxia, metabolism, extracellular redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, intriguing model that asbestos-associated pathogenesis includes excess environment during carcinogenesis. Re-analysis rat asbestos-induced MM revealed inverse between high CA9 expression survival. Here we used human MMs to identify molecular events surrounding from viewpoint metabolism. was significantly higher than MeT-5A mesothelial cells, which further amplified hypoxia (1%O2) increased catalytic Fe(II). suppression by inhibitors (S4 U104) decreased viability migration accompanied overexpression TFRC, IREB1/2 FPN1(SLC40A1) downregulation FTH/FTL. This expressional pattern similar erastin-induced ferroptosis same Furthermore, observed mitochondrial fission enhanced autophagy Fe(II) both mitochondria lysosomes after inhibition, peroxides, O2- lipid peroxidation. The eventual cell death inhibited deferoxamine, ferrostatin-1 Z-VAD-FMK, suggesting mixed apoptosis. Therefore, plays role metabolism regulation

Language: Английский

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How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

Cancers, Journal Year: 2020, Volume and Issue: 12(6), P. 1616 - 1616

Published: June 18, 2020

The acidic tumour microenvironment is now recognized as a phenotype that drives cancer somatic evolution and disease progression, causing cells to become more invasive metastasise. This property of solid tumours reflects complex interplay between cellular carbon metabolism acid removal mediated by cell membrane carbonic anhydrases various transport proteins, interstitial fluid buffering, abnormal tumour-associated vessels. In the past two decades, convergence advances in experimental mathematical modelling human cancers, well non-invasive pH-imaging techniques, has yielded new insights into physiological mechanisms govern extracellular pH (pHe). this review, we examine which maintain low pHe, with focus on anhydrase IX (CAIX), cancer-associated surface enzyme. We also review accumulating evidence suggest role for CAIX biological pH-stat stabilize their pHe. Finally, highlight prospects clinical translation CAIX-targeted therapies oncology.

Language: Английский

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Lactate and Acidity in the Cancer Microenvironment

Annual Review of Cancer Biology, Journal Year: 2019, Volume and Issue: 4(1), P. 141 - 158

Published: Nov. 20, 2019

Fermentative glycolysis, an ancient evolved metabolic pathway, is exploited by rapidly growing tissues and tumors but also occurs in response to the nutritional energetic demands of differentiated tissues. The lactic acid it produces transported across cell membranes through reversible H + /lactate − symporters (MCT1 MCT4) recycled organs as a major precursor gluconeogenesis energy source. Concentrations lactate tumor environment, investigated utilizing induced bioluminescence imaging (imBI) technique, appear be dominant biomarkers irradiation resistance treatment. Suppression formation genetic disruption dehydrogenases A B aggressive reactivated OXPHOS (oxidative phosphorylation) maintain xenograft growth at halved rate. In contrast, transporters MCT1/4 suppressed mTORC1, result intracellular acidosis. Furthermore, global reduction acidity contributes activation antitumor immune responses, offering hope for future clinical applications.

Language: Английский

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Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

BMC Cancer, Journal Year: 2020, Volume and Issue: 20(1)

Published: April 15, 2020

Abstract Background Given the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, main physiological functions of left right colons, tumor location is increasingly suggested to dictate behavior affecting pathology, progression prognosis. Right-sided colon cancers arise cecum, ascending colon, hepatic flexure and/or transverse while left-sided splenic flexure, descending, sigmoid colon. In contrast prior reports, we attempt delineate programs tumorigenesis independently for each side. Methods Four hundred eleven samples were extracted from The Cancer Genome Atlas-COAD cohort, based on a conservative sample inclusion criterion. Each side was analyzed with respect their respective normal tissue, at level transcription, post-transcription, miRNA control methylation both stage specific stage-agnostic manner. Results Our results indicate suppression enzymes involved various stages carcinogen breakdown including CYP2C8 , CYP4F12 GSTA1 UGT1A within tumors. This implies its reduced capacity detoxify carcinogens, contributing genotoxic environment, subsequently more aggressive phenotype. Additionally, highlight crucial nexus between calcium homeostasis (sensing, mobilization absorption) immune/GPCR signaling tumors, possibly proliferative metastatic potential. Interestingly, two genes SLC6A4 HOXB13 show opposing regulatory trends Post-transcriptional regulation mediated by RNA-binding proteins (e.g. NKRF (in left) MSI2 right)) miRNAs miR-29a left); miR-155, miR181-d, miR-576 miR23a appear exhibit side-specificity target transcripts pronounced depict location-specific differences, increased hypomethylation open seas hypermethylation CpG islands Conclusions Differences molecular mechanisms captured here distinctions which will serve as basis future studies, influencing efficacies existing diagnostic, prognostic therapeutic interventions.

Language: Английский

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The therapeutic importance of acid-base balance

Biochemical Pharmacology, Journal Year: 2020, Volume and Issue: 183, P. 114278 - 114278

Published: Oct. 9, 2020

Language: Английский

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