CAXII

To achieve better-repurposed motifs, saccharin has been merged with biocompatible sugar molecules via a 1,2,3-triazole linker, and ten novel 1,2,3-triazole-appended saccharin glycoconjugates were developed in good yield by utilizing modular CuAAC click as regioselective triazole forming tool. The docking study indicated that the resulting hybrid molecules have an overall substantial interaction with the CAXII macromolecule. Moreover, the galactose triazolyl saccharin analogue 3h has a binding energy of -8.5 kcal/mol with 5 H-bonds, and xylosyl 1,2,3-triazolyl saccharin analogue 3d has a binding energy of -8...

Melanoma is the principal cause of death in skin cancer due to its ability to invade and cause metastasis. Hypoxia, which characterises the tumour microenvironment (TME), plays an important role in melanoma development, as cancer cells can adapt and acquire a more aggressive phenotype. Carbonic anhydrases (CA) activity, involved in pH regulation, is related to melanoma cell migration and invasion. Furthermore, the Hedgehog (Hh) pathway, already known for its role in physiological processes, is a pivotal character in cancer cell growth and can represent a promising pharmacological target...

BACKGROUND: Resveratrol's structural similarity to commercialized anti-breast cancer medications such as Tamoxifen underlines its potential as a promising option for developing successful anti-breast cancer drugs. However, the pharmacokinetic issues associated with resveratrol, such as its low bioavailability, have piqued the attention of researchers in developing novel derivatives. METHOD: A novel phytoalexin derivative, RsvD1, was successfully synthesized using resveratrol extracted from green grape peels as a precursor to investigate its anti-breast cancer efficacy on Estrogen receptor (ER) positive and negative breast cancer cells...

Hepatocellular carcinoma (HCC) is a lethal malignancy with a lack of effective treatments particularly for the disease at an advanced stage. Even though immune checkpoint inhibitors (ICIs) have made great progress in the treatment of HCC, durable and ideal clinical benefits still cannot be achieved in plenty of patients with HCC. Therefore, novel and refined ICI-based combination therapies are still needed to enhance the therapeutic effect. The latest study has reported that the carbonic anhydrase XII inhibitor (CAXIIi), a novel type of anticancer drug, can modify the tumor immunosuppression microenvironment by affecting hypoxic/acidic metabolism and alter the functions of monocytes and macrophages by regulating the expression of C-C motif chemokine ligand 8 (CCL8)...

Tumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (CRC). CRC can be classified into four different consensus molecular subgroups (CMS) showing unique expression patterns and molecular traits. We questioned whether there is a CMS-related CAIX/CAXII expression pattern in CRC predicting response...

In recent years, molecular hybridization strategies have developed into a potent strategy for drug discovery. A series of novel thiopyrano[2,3- d ]thiazoles linked to the pyrazole moiety was designed and developed as anticancer agents by a molecular hybridization. Target compounds were synthesized and characterized by spectroscopic tools as well as X-ray crystallography analysis as in the case of thiopyrano[2,3- d ]thiazole derivative 5a . The MTT assay was used to demonstrate the in vitro efficacy of compounds 5a - g and 7a - j on MCF-7 and HePG-2...

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. In this preclinical study, we examines Tiliroside (TS, C30 H26 O13 ), as one of the major compounds of Tribulus terrestris L. which has been used as an alternative therapy in clinic practice of breast cancer treatment, for its therapeutic use in TNBC. The association between CAXII expression level and survival probability of TNBC patients, and the difference of CAXII expression level between TNBC and normal samples were evaluated by using publicly accessible databases...

Estrogen receptor alpha (ERα) expression in ~2/3 breast tumors selects patients for hormonal therapies. Tumors negative for ERα but positive for the progesterone receptor (PR, encoded by PGR ) have also been candidates for ER-targeting therapies, as PR expression may reflect undetected ER activity. Conversely, PR- status in ER+ tumors predicts a worse therapeutic response. Our analysis of breast tumor transcriptome datasets, however, revealed that in tumors with lower PGR expression, the clinical PR status does not correlate accurately with the expression of ESR1 or of ER target genes, including PGR itself...

Ectodomain shedding is a form of limited proteolysis in which a protease cleaves a transmembrane protein, releasing the extracellular domain from the cell surface. Cells use this process to regulate a wide variety of biological events. Typically, immunological detection methods are employed for the analysis of ectodomains secreted into the cultured media. In this paper, we describe a new strategy using an affinity-based protein-labeling fluorescent probe to study ectodomain shedding. We analyzed the ectodomain shedding of cell surface carbonic anhydrases (CAIX and CAXII), which are important biomarkers for tumor hypoxia...

BACKGROUND: Malignant melanoma is the leading cause of death among skin cancer patients due to its tendency to metastasize. Alterations at the molecular level are often evident, which is why melanoma biology has garnered increasing interest. The hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly re-activated in melanoma and may represent a promising therapeutic target. In addition, carbonic anhydrase XII (CAXII) represents a poor prognostic target for hypoxic tumors, such as melanoma, and is involved in cell migration...

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with a release of the proton. CA, especially CAIX and CAXII isoforms gained the attention of many researchers interested in anticancer drug design due to pivotal functions of enzymes in the cancer cell metastasis and response to hypoxia, and their expression restricted to malignant cells. This offers an opportunity to develop new targeted therapies with fewer side effects...

Neuroblastoma is a rare disease. Rare are also the possibilities to test new therapeutic options for neuroblastoma in clinical trials. Despite the constant need to improve therapy and outcomes for patients with advanced neuroblastoma, clinical trials currently only allow for testing few substances in even fewer patients. This increases the need to improve and advance preclinical models for neuroblastoma to preselect favorable candidates for novel therapeutics. Here we propose the use of a new patient-derived 3D slice-culture perfusion-based 3D model in combination with rapid treatment evaluation using isothermal microcalorimetry exemplified with treatment with the novel carbonic anhydrase IX and XII (CAIX/CAXII) inhibitor SLC-0111...

Non-ampullary duodenal adenocarcinoma (DAC) is a rare malignancy. Little information is available concerning the histopathological prognostic factors associated with DAC. Carbonic anhydrases (CAs) are metalloenzymes catalyzing the universal reaction of CO2 hydration. Isozymes CAII, CAIX, and CAXII are associated with prognosis in various cancers. Our aim was to analyze the immunohistochemical expressions of CAII, CAIX, and CAXII in normal duodenal epithelium, duodenal adenomas, and adenocarcinoma and their associations with clinicopathological variables and survival...

BACKGROUND: The pathogenesis of gastroesophageal reflux disease (GERD) has not been resolved in detail. Esophageal epithelial cells provide resistance to acidic reflux via several mechanisms, many of which involve buffering acid with bicarbonate and transporting protons. Carbonic anhydrases (CAs) are enzymes that control the acid-base balance by catalyzing the reversible hydration of carbon dioxide to produce bicarbonate and hydrogen ions. AIMS: We aimed to determine the immunohistochemical expression patterns of CAII, CAIX, and CAXII in the normal esophageal squamous epithelium and in patients with GERD...

Liver cancer is the fatal cause of cancer deaths worldwide due to its aggressiveness and lack of effective therapies. Tiliroside (C30 H26 O13 ) is an active compound extracted from herb plant Tribulus terrestris L., which has been used as alternative therapy in clinic practice. However, its therapeutic use against liver cancer has not been previously reported. Here, we showed that Tiliroside exerted significantly higher anti-proliferation effect on liver cancer cell lines Hep3B and SNU-449 than on liver normal cell THLE-3 cells or NC group, respectively, by using MTS assay...

Background: The metabolic enzyme carbonic anhydrase 12 (CA12/CAXII) emerges as a promising cancer therapeutic target with drug development projects underway. Previous reports proposed the relevance of CA12 in the context of glioma but are limited in patient data quantity, ignore ethnic diversity of patients or rely on semi-quantitative, thereby out of date, methodology. Moreover, little is known on the association of CA12 to brain tumor stemness or on the effect of anti-CAXII-directed monotherapies on glioma stem cells (GSCs), in particular their response regarding mesenchymal differentiation status...

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC...

The reverse pH gradient is a major feature associated with cancer cell reprogrammed metabolism. This phenotype is supported by increased activity of pH regulators like ATPases, carbonic anhydrases (CAs), monocarboxylate transporters (MCTs) and sodium-proton exchangers (NHEs) that induce an acidic tumor microenvironment, responsible for the cancer acid-resistant phenotype. In this work, we analyzed the expression of these pH regulators and explored their inhibition in breast cancer cells as a strategy to enhance the sensitivity to chemotherapy...

Carbonic anhydrase IX (CAIX) is considered a target for therapeutic intervention in solid tumors. In this study, the efficacy of the inhibitor, 4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl)benzenesulfonamide (SLC-149), is evaluated on CAIX and a CAIX-mimic. We show that SLC-149 is a better inhibitor than acetazolamide against CAIX. Binding of SLC-149 thermally stabilizes CAIX-mimic at lower concentrations compared to that of CAII. Structural examinations of SLC-149 bound to CAIX-mimic and CAII explain binding preferences...

BACKGROUND: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but they have not been correlated before and/or identified as a potential pharmacological target. Here, for the first time, we demonstrated that malignant melanoma cell motility was impaired by targeting CAXII via either CAs inhibitors or through the inhibition of the Hh pathway...