The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond

Cancer and Metastasis Reviews, Journal Year: 2019, Volume and Issue: 38(1-2), P. 65 - 77

Published: May 10, 2019

Cancer development is a complex process that follows an intricate scenario with dynamic interplay of selective and adaptive steps extensive cast molecules signaling pathways. Solid tumor initially grows as avascular bulk cells carrying oncogenic mutations until diffusion distances from the nearest functional blood vessels limit delivery nutrients oxygen on one hand removal metabolic waste other one. These restrictions result in regional hypoxia acidosis select for adaptable able to promote aberrant angiogenesis, remodel metabolism, acquire invasiveness metastatic propensity, gain therapeutic resistance. Tumor are thereby endowed capability survive proliferate hostile microenvironment, communicate stroma, enter circulation, colonize secondary sites, generate metastases. While role initializing driving these processes well established, key contribution non-genomic, landscaping molecular players still less appreciated despite they can equally serve viable targets anticancer therapies. Carbonic anhydrase IX (CA IX) players: it induced by hypoxia, functionally linked acidosis, implicated invasiveness, correlated Here, we summarize available experimental evidence supported accumulating preclinical clinical data CA contribute virtually each step cancer progression path via its enzyme activity and/or non-catalytic mechanisms. We also propose targeting express may provide benefits various settings combinations both conventional newly developed treatments.

Language: Английский

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Signal transduction via integrin adhesion complexes

Current Opinion in Cell Biology, Journal Year: 2018, Volume and Issue: 56, P. 14 - 21

Published: Sept. 5, 2018

Language: Английский

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Carbonic Anhydrases: Role in pH Control and Cancer

Metabolites, Journal Year: 2018, Volume and Issue: 8(1), P. 19 - 19

Published: Feb. 28, 2018

The pH of the tumor microenvironment drives metastatic phenotype and chemotherapeutic resistance tumors. Understanding mechanisms underlying this pH-dependent phenomenon will lead to improved drug delivery allow identification new therapeutic targets. This includes an understanding role plays in primary cells, regulatory factors that permit cancer cells thrive. Over last decade, carbonic anhydrases (CAs) have been shown be important mediators cell by modulating bicarbonate proton concentrations for survival proliferation. has prompted effort inhibit specific CA isoforms, as anti-cancer strategy. Of 12 active two, IX XII, considered However, other isoforms also show similar activity tissue distribution cancers not targets treatment. In review, we consider all their possible tumors potential therapy.

Language: Английский

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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 Inhibition and the Management of Hypoxic Tumors

Metabolites, Journal Year: 2017, Volume and Issue: 7(3), P. 48 - 48

Published: Sept. 16, 2017

Hypoxia and acidosis are salient features of many tumors, leading to a completely different metabolism compared normal cells. Two the simplest metabolic products, protons bicarbonate, generated by catalytic activity metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), with at least two its isoforms, CA IX XII, mainly present in hypoxic tumors. Inhibition tumor-associated CAs leads an impaired growth primary metastases reduces population cancer stem cells, thus complex beneficial anticancer action for this class enzyme inhibitors. In review, I will state art on development inhibitors (CAIs) targeting which may have applications treatment imaging cancers expressing them. Small molecule inhibitors, one (SLC-0111) completed Phase clinical trials, antibodies (girentuximab, discontinued III trials) be discussed, together various approaches used design agents new mechanism based interference these crucial metabolites, bicarbonate.

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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Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia

Gastroenterology, Journal Year: 2019, Volume and Issue: 157(3), P. 823 - 837

Published: May 9, 2019

Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, are refractory to chemo radiation therapies. To survive in the environment, PDAC cells upregulate enzymes transporters involved pH regulation, including extracellular facing carbonic anhydrase 9 (CA9). We evaluated effect blocking CA9, combination with administration gemcitabine, mouse models cancer.We knocked down expression KRAS human (PK-8 PK-1) small hairpin RNAs. Human (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) were incubated inhibitors MEK (trametinib) or signal-regulated kinase (ERK), some cultured under conditions. measured levels stability hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain protein (EPAS1, also called HIF2A), solute carrier family 16 member 4 (SLC16A4, MCT4), SLC2A1 (also GLUT1) by immunoblot analyses. analyzed intracellular (pHi) metabolic flux. CA9 cells, inhibited SLC-0111, them assessed pHi, flux, cytotoxicity normoxic Cells injected into either immune-compromised immune-competent mice growth xenograft tumors was assessed. Tumor fragments derived from patients surgically ligated pancreas performed tissue microarray analyses 205 samples measure associated genes that regulate hypoxia outcomes using Cancer Genome Atlas database.Under conditions, had increased HIF1A HIF2A, upregulated glycolysis. Knockdown incubation trametinib, reduced posttranscriptional stabilization upregulation glycolysis response hypoxia. expressed 66% analyzed; high adaptation hypoxia, correlated significantly survival times patients. pharmacologic inhibition pHi decreased gemcitabine-induced glycolysis, their sensitivity gemcitabine. knockdown formed smaller mice, injection gemcitabine tumor mice. In grown oral SLC-0111 intratumor acidosis cell death. These tumors, patient-derived fragments, grew more slowly than given control agents, resulting longer times. KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified numbers B tumors.In increase via Disruption this pathway slows might be developed for treatment cancer.

Language: Английский

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Amorphous Fe‐Based Nanoagents for Self‐Enhanced Chemodynamic Therapy by Re‐Establishing Tumor Acidosis

Advanced Functional Materials, Journal Year: 2019, Volume and Issue: 30(6)

Published: Nov. 29, 2019

Abstract Chemodynamic therapy (CDT) by introducing the Fenton‐/Fenton‐like reaction in an acidic and H 2 O environment for toxic hydroxyl radical (•OH) generation, is a newly developed tumor‐selective therapeutic. However, tumor acidosis, characterized extracellular acidity (pH e ≈ 6.5) intracellular alkalinity i 7.2), undoubtedly confers large chemical barrier effective implementation of CDT thus limits its functional activity therapeutic efficacy. Here, unique amorphous iron nanoparticles (AFeNPs) loaded with carbonic anhydrase IX inhibitor (CAI) are constructed to re‐establish acidosis decreased pH increased via inhibiting over‐expressed CA cancer cells CAI self‐enhanced CDT. The suppression leads + accumulation that could accelerate AFeNPs‐based Fenton drastically exacerbate oxidative stress subsequently induce cell death; meanwhile, inhibition formation outside efficiently represses potential invasion metastasis owing insufficient ions degradation matrix. Re‐established not only assists optimization CDT, but also presents opportunity development new antitumor methods more tumor‐acidity specific.

Language: Английский

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Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Metabolites, Journal Year: 2020, Volume and Issue: 10(10), P. 412 - 412

Published: Oct. 14, 2020

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence outcome anticancer therapies. rationale behind many these phenomena resides in activation transcription factors such as hypoxia-inducible factor 1 2 (HIF-1/2). In turn, HIF pathway activates a number genes including those involved glucose metabolism, angiogenesis, pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, CA IX XII, actively participate processes were validated antitumor/antimetastatic drug targets. Here, we review field inhibitors (CAIs), selectively inhibit cancer-associated isoforms. Particular focus was on identification lead compounds various inhibitor classes, measurement inhibitory on-/off-target effects. addition, preclinical data that resulted SLC-0111, sulfonamide Phase Ib/II clinical trials treatment hypoxic, advanced solid tumors, are detailed.

Language: Английский

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Carbonic anhydrases in metazoan model organisms: molecules, mechanisms, and physiology

Physiological Reviews, Journal Year: 2022, Volume and Issue: 102(3), P. 1327 - 1383

Published: Feb. 15, 2022

During the past three decades, mice, zebrafish, fruit flies, and Caenorhabditis elegans have been primary model organisms used for study of various biological phenomena. These models also adopted developed to investigate physiological roles carbonic anhydrases (CAs) anhydrase-related proteins (CARPs). belong eight CA families are identified by Greek letters: α, β, γ, δ, ζ, η, θ, ι. Studies using focused on two families, α-CAs β-CAs, which expressed in both prokaryotic eukaryotic with species-specific distribution patterns unique functions. This review covers CAs CARPs light investigations performed organisms. Functional studies demonstrate that not only linked regulation pH homeostasis, classical role CAs, but contribute a plethora previously undescribed

Language: Английский

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