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Carbonic anhydrase XII as biomarker and therapeutic target in ovarian carcinomas.

ABSTRACT: Targeting the tumor-associated carbonic anhydrase XII (CA XII) is considered a promising strategy to improve cancer treatment. As such progress is highly demanded for ovarian carcinomas, the present study aimed to provide deeper information about their CA XII expression profile. A large collection of tissue specimens was stained immunohistochemically with a specific anti-CA XII antibody to evaluate the expression in neoplastic and non-neoplastic epithelial ovarian cells. In addition, flow cytometry was used to measure CA XII expression on tumor cells from malignant ascites fluid. Binding of the antibody revealed a significant CA XII expression in most ovarian carcinoma tissue samples and ascites-derived ovarian carcinoma cells. Moreover, CA XII was expressed at higher levels in ovarian carcinomas as compared to borderline ovarian tumors and non-neoplastic ovarian epithelia. Within the carcinoma tissues, high expression of CA XII was associated with higher tumor grading and a trend towards shorter overall survival. Our results indicate that CA XII plays a crucial role for the malignancy of ovarian carcinoma cells and emphasize the potential of CA XII as a diagnostic marker and therapeutic target in the management of ovarian carcinomas.

SUBMITTER: Hiepp L

PROVIDER: S-EPMC9333239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells.

Project description:Multidrug resistance (MDR) in cancer cells is a challenging phenomenon often associated with P-glycoprotein (Pgp) surface expression. Finding new ways to bypass Pgp-mediated MDR still remains a daunting challenge towards the successful treatment of malignant neoplasms such as colorectal cancer.We applied the Cell Surface Capture technology to chemosensitive and chemoresistant human colon cancer to explore the cell surface proteome of Pgp-expressing cells in a discovery-driven fashion. Comparative quantitative analysis of identified cell surface glycoproteins revealed carbonic anhydrase type XII (CAXII) to be up-regulated on the surface of chemoresistant cells, similarly to Pgp. In cellular models showing an acquired MDR phenotype due to the selective pressure of chemotherapy, the progressive increase of the transcription factor hypoxia-inducible factor-1 alpha was paralleled by the simultaneous up-regulation of Pgp and CAXII. CAXII and Pgp physically interacted at the cell surface. CAXII silencing or pharmacological inhibition with acetazolamide decreased the ATPase activity of Pgp by altering the optimal pH at which Pgp operated and promoted chemosensitization to Pgp substrates in MDR cells.We propose CAXII as a new secondary marker of the MDR phenotype that influences Pgp activity directly and can be used as a pharmacological target for MDR research and potential treatment.

| S-EPMC4466649 | biostudies-literature

Ureidobenzenesulfonamides as Selective Carbonic Anhydrase I, IX, and XII Inhibitors.

Project description:Sulfonamides remain an important class of drugs, especially because of their inhibitory effects on carbonic anhydrases. Herein, we have synthesized several sulfonamides and tested them for their inhibitory activity against carbonic anhydrases hCA I, hCA II, hCA IX, and hCA XII, respectively. Thereby, biphenyl- and benzylphenyl-substituted sulfonamides showed high selectivity against hCA IX and hCA XII; these enzymes are common targets in the treatment of hypoxic cancers, and noteworthy inhibitory activity was observed for several compounds toward hCA I that might be of interest for future applications to treat cerebral edema. Compound 3 (4-[3-(2-benzylphenyl)ureido]benzenesulfonamide) held an exceptionally low Ki value of 1.0 nM for hCA XII.

| S-EPMC10707797 | biostudies-literature

Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII.

Project description:Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO? hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).

| S-EPMC2978943 | biostudies-literature

P-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors.

Project description:Carbonic anhydrase XII (CAXII) is a membrane enzyme that maintains pH homeostasis and sustains optimum P-glycoprotein (Pgp) efflux activity in cancer cells. Here, we investigated a panel of eight CAXII inhibitors (compounds 1-8), for their potential to reverse Pgp mediated tumor cell chemoresistance. Inhibitors (5 nM) were screened in human and murine cancer cells (colon, lung, breast, bone) with different expression levels of CAXII and Pgp. We identified three CAXII inhibitors (compounds 1, 2 and 4) that significantly (≥ 2 fold) increased the intracellular retention of the Pgp-substrate and chemotherapeutic doxorubicin, and restored its cytotoxic activity. The inhibitors lowered intracellular pH to indirectly impair Pgp activity. Ca12-knockout assays confirmed that the chemosensitizing property of the compounds was dependent on active CAXII. Furthermore, in a preclinical model of drug-resistant breast tumors compound 1 (1900 ng/kg) restored the efficacy of doxorubicin to the same extent as the direct Pgp inhibitor tariquidar. The expression of carbonic anhydrase IX had no effect on the intracellular doxorubicin accumulation. Our work provides strong evidence that CAXII inhibitors are effective chemosensitizer agents in CAXII-positive and Pgp-positive cancer cells. The use of CAXII inhibitors may represent a turning point in combinatorial chemotherapeutic schemes to treat multidrug-resistant tumors.

| S-EPMC5349880 | biostudies-literature

Switching the Inhibitor-Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII.

Project description:A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti-cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure-based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors.

| S-EPMC8095314 | biostudies-literature

Exploring Heteroaryl-pyrazole Carboxylic Acids as Human Carbonic Anhydrase XII Inhibitors.

Project description:We report the synthesis, biological evaluation, and structural study of a series of substituted heteroaryl-pyrazole carboxylic acid derivatives. These compounds have been developed as inhibitors of specific isoforms of carbonic anhydrase (CA), with potential as prototypes of a new class of chemotherapeutics. Both X-ray crystallography and computational modeling provide insights into the CA inhibition mechanism. Results indicate that this chemotype produces an indirect interference with the zinc ion, thus behaving differently from other related nonclassical inhibitors. Among the tested compounds, 2c with Ki = 0.21 μM toward hCA XII demonstrated significant antiproliferative activity against hypoxic tumor cell lines. Taken together, the results thus provide the basis of structural determinants for the development of novel anticancer agents.

| S-EPMC5601383 | biostudies-literature

Advances in Anti-Cancer Drug Development Targeting Carbonic Anhydrase IX and XII.

Project description:The microenvironment within a solid tumor is heterogeneous with regions being both acidic and hypoxic. As a result of this, cancer cells upregulate genes that allow survival in such environments. Some of these genes are pH regulatory factors, including carbonic anhydrase IX (CA IX) and in some cases XII (CA XII). CA IX helps to maintain normal cytoplasmic pH (pHi) while simultaneously contributing to the extracellular pH (pHe). CA XII is also thought to be responsible for stabilizing pHe at physiological conditions. Extracellular acidification of the tumor microenvironment promotes local invasion and metastasis while decreasing the effectiveness of adjuvant therapies, thus contributing to poor cancer clinical outcomes. In this review, we describe the properties of CA IX and CA XII that substantiate their potential use as anticancer targets. We also discuss the current status of CA isoform-selective inhibitor development and patents of CA IX/XII targeted inhibitors that show potential for treating aggressive tumors. Some of the recently published patents discussed include sulfonamide-based small molecule inhibitors including derivatives of boron cluster compounds; metal complexes of poly(carboxyl)amine-containing ligands; nitroi-midazole-, ureidosulfonamide-, and coumarin-based compounds; as well as G250 and A610 monoclonal antibodies for cancer treatment.

| S-EPMC6162069 | biostudies-literature

Molecular Cloning and Characterization of Carbonic Anhydrase XII from Pufferfish (Takifugu rubripes).

Project description:In this study, an 1888-bp carbonic anhydrase XII (CA XII) sequence was cloned from the brain of the pufferfish, Takifugu rubripes. The cloned sequence contained a coding region of 1470-bp, which was predicted to translate into a protein of 490 amino acid residues. The predicted protein showed between 68-56% identity with the large yellow croaker (Larimichthys crocea), tilapia (Oreochromis niloticus), and Asian arowana (Scleropages formosus) CA XII proteins. It also exhibited 36% and 53% identity with human CA II and CA XII, respectively. The cloned sequence contained a 22 amino acid NH₂-terminal signal sequence and three Asn-Xaa-Ser/Thr sequons, among which one was potentially glycosylated. Four cysteine residues were also identified (Cys-21, Cys-201, Cys-355, and Cys-358), two of which (Cys-21 and Cys-201) could potentially form a disulfide bond. A 22-amino acid COOH-terminal cytoplasmic tail containing a potential site for phosphorylation by protein kinase A was also found. The cloned sequence might be a transmembrane protein, as predicted from in silico and phylogenetic analyses. The active site analysis of the predicted protein showed that its active site residues were highly conserved with tilapia CA XII protein. Homology modeling of the pufferfish CA XII was done using the crystal structure of the extracellular domain of human carbonic anhydrase XII at 1.55 Å resolution as a template. Semi-quantitative reverse transcription (RT)-PCR, quantitative PCR (q-PCR), and in situ hybridization confirmed that pufferfish CA XII is highly expressed in the brain.

| S-EPMC5877703 | biostudies-literature

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives.

Project description:A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors.

| S-EPMC7899656 | biostudies-literature

Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII.

Project description:A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.

| S-EPMC6429297 | biostudies-literature

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