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2022 ◽  
Vol 23 (2) ◽  
pp. 879
Author(s):  
Katarina Grossmannova ◽  
Monika Barathova ◽  
Petra Belvoncikova ◽  
Viliam Lauko ◽  
Lucia Csaderova ◽  
...  

Abdominal aortic aneurysms (AAA) are a significant cause of premature deaths worldwide. Since there is no specific treatment for reducing AAA progression, it is crucial to understand the pathogenesis leading to aneurysm wall weakening/remodeling and identify new proteins involved in this process which could subsequently serve as novel therapeutic targets. In this study, we analyzed the presence of the hypoxia-related proteins carbonic anhydrase IX (CA IX), hypoxia-inducible factor 1α (HIF-1α), and AKT as the key molecule in the phosphoinositide-3-kinase pathway in the AAA wall. Additionally, we used a blood-based assay to examine soluble CA IX (s-CA IX) levels in the plasma of AAA patients. Using western blotting, we detected CA IX protein in 12 out of 15 AAA tissue samples. Immunohistochemistry staining proved CA IX expression in the media of the aneurysmal wall. Evaluation of phosphorylated (p-AKT) and total AKT showed elevated levels of both forms in AAA compared to normal aorta. Using ELISA, we determined the concentration of s-CA IX >20 pg/mL in 13 out of 15 AAA patients. Results obtained from in silico analysis of CA9 and aneurysm-associated genes suggest a role for CA IX in aneurysmal wall remodeling. Our results prove the presence of hypoxia-related CA IX in AAA tissues and indicate a possible role of CA IX in hypoxia-associated cardiovascular diseases.


2021 ◽  
Vol 22 (24) ◽  
pp. 13610
Author(s):  
Zuopeng Zhang ◽  
Huali Yang ◽  
Ye Zhong ◽  
Yueqing Wang ◽  
Jian Wang ◽  
...  

Based on the strategy of the “tail approach”, 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds showed good activity against CAs and high topological polar surface area (TPSA) values, which had a positive effect on the selective inhibition of transmembrane isoforms CA IX and XII. In the in vitro activity studies, compounds 16a, 16b, and 16e reduced the viability of HT-29 and MDA-MB-231 cells with a high expression of CA IX under hypoxia. The inhibitory activity of compound 16e on the human osteosarcoma cell line MG-63 with a high expression of CA IX and XII was better than that of AZM. Moreover, high concentrations of compounds 16a and 16b reversed the acidification of the tumour microenvironment. In addition, compound 16a had a certain inhibitory effect on the migration of MDA-MB-231 cells. All the above results indicate that the saccharide-modified sulfonamide has further research value for the development of CA IX inhibitors.


2021 ◽  
Vol 22 (24) ◽  
pp. 13405
Author(s):  
Stanislav Kalinin ◽  
Anna Malkova ◽  
Tatiana Sharonova ◽  
Vladimir Sharoyko ◽  
Alexander Bunev ◽  
...  

Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant therapeutic agents. Thus, hypoxia and extracellular acidosis are known to select for the most aggressive and resilient phenotypes and build poorly responsive regions of the tumor mass. Carbonic anhydrase (CA, EC 4.2.1.1) IX isoform is a surficial zinc metalloenzyme that is proven to play a central role in regulating intra and extracellular pH, as well as modulating invasion and metastasis processes. With its strong association and distribution in various tumor tissues and well-known druggability, this protein holds great promise as a target to pharmacologically interfere with the tumor microenvironment by using drug combination regimens. In the present review, we summarized recent publications revealing the potential of CA IX inhibitors to intensify cancer chemotherapy and overcome drug resistance in preclinical settings.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Martin Proescholdt ◽  
Zhenwei Qiu ◽  
Johannes Falter ◽  
Anette Lohmeier ◽  
Nils-Ole Schmidt

Abstract BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti – invasive treatment. METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p < 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p < 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.


QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Moataz Mohamed Sayed ◽  
Mohamed Lotfy Soliman ◽  
Yomna Mohamed Tamim ◽  
Ahmed H Osman ◽  
Muhammad Saleh Abdul-Rasheed Hussain

Abstract Background Despite the progress achieved in early detection and treatment of HCC, it still accounts for a significant number of cancer-related deaths worldwide. Tumoral microenvironment acidity plays a pivotal role in tumoral cell survival, tumoral progression and metastasis. CA-IX and XII are two of several mechanisms by which tumor maintain optimal intracellular pH at the expense of the extracellular environment that turns into acidic pH. ACT is a CA inhibitor that is used in many medical indications. It is effective, safe and inexpensive. It has some side effects and it may be even contraindicated in some cases. Aim of the work To evaluate the possible anticarcinogenic role of ACT in DEN-induced HCC animal model. Materials and Methods This study showed that using DEN for 10 weeks caused significant increase in the levels of AST, ALT, total bilirubin, direct bilirubin and AFP and significant decrease in albumin level in DEN-induced HCC rat groups when compared to normal control rats. Administration of ACT for 3 weeks in ACT-treated DEN-induced HCC group caused marked improvement in the mentioned biochemical measurements (AST, ALT, total bilirubin, direct bilirubin and AFP) when compared to DEN-induced HCC rat group without ACT treatment, yet still higher than the lab values of normal control group. Results The present study demonstrated that using DEN in rat groups had induced polyhedral to round hepatocytes with dense, centrally located vesicular nuclei. The neoplastic areas showed poorly differentiated large cells with hyperchromatic nuclei and prominent nucleoli. The neoplastic cells showed anisokaryosis, anisocytosis, and deeply basophilic scanty cytoplasm and frequent mitotic figures mostly Grade III. The hepatic lobule displayed disorganization of hepatic cords with hyperplasia of Kupffer cells, multinucleated tumor giant cells with prominent basophilic nuclei and basophilic spindle cells. Conclusion Acetazolamide showed significant antitumor effect in DEN-induced HCC in rats, making it a promising agent to use against HCC either individually or in combination with any other therapeutic modalities. Further researches should be conducted in this anti HCC aspect.


2021 ◽  
Vol 9 ◽  
Author(s):  
Nancy Huntly ◽  
Audrey R. Freischel ◽  
Anna K. Miller ◽  
Mark C. Lloyd ◽  
David Basanta ◽  
...  

Over 40 years ago, seminal papers by Armstrong and McGehee and by Levins showed that temporal fluctuations in resource availability could permit coexistence of two species on a single resource. Such coexistence results from non-linearities or non-additivities in the way resource supply translates into fitness. These reflect trade-offs where one species benefits more than the other during good periods and suffers more (or does less well) than the other during less good periods, be the periods stochastic, unstable population dynamics, or seasonal. Since, coexistence based on fluctuating conditions has been explored under the guises of “grazers” and “diggers,” variance partitioning, relative non-linearity, “opportunists” and “gleaners,” and as the storage effect. Here we focus on two phenotypes, “cream skimmers” and “crumb pickers,” the former having the advantage in richer times and the latter in less rich times. In nature, richer and poorer times, with regular or stochastic appearances, are the norm and occur on many time scales. Fluctuations among richer and poorer times also appear to be the norm in cancer ecosystems. Within tumors, nutrient availability, oxygen, and pH can fluctuate stochastically or periodically, with swings occurring over seconds to minutes to hours. Despite interest in tumor heterogeneity and how it promotes the coexistence of different cancer cell types, the effects of fluctuating resource availability have not been explored for cancer. Here, in the context of pulsed resources, we (1) develop models of foraging consumers who experience pulsed resources to examine four types of trade-offs that can promote coexistence of phenotypes that do relatively better in richer versus in poorer times, (2) establish that conditions in tumors are conducive for this mechanism, (3) propose and empirically explore biomarkers indicative of the two phenotypes (HIF-1, GLUT-1, CA IX, CA XII), and (4) and compare cream skimmer and crumb picker biology and ecology in nature and cancer to provide cross-disciplinary insights into this interesting, and, we argue, likely very common, mechanism of coexistence.


2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii35-ii35
Author(s):  
M Proescholdt ◽  
Z Qiu ◽  
J Falter ◽  
N Schmidt

Abstract BACKGROUND Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti - invasive treatment. MATERIAL AND METHODS Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot. RESULTS Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p < 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p < 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition. CONCLUSION Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.


2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii57-ii58
Author(s):  
E R Burgess ◽  
R L I Crake ◽  
E Phillips ◽  
H R Morrin ◽  
J A Royds ◽  
...  

Abstract BACKGROUND Gliomas are the most common brain cancer and survival is poor, with 11–15 months for high-grade glioblastoma patients, despite treatment. Gliomas are hypoxic tumours, which increases with tumour grade. Under hypoxia, the transcription factor hypoxia inducible factor-1 (HIF) accumulates and upregulates expression of genes involved in tumour development and progression. HIF-1 levels and activity are controlled by HIF hydroxylases which target HIF-1α for degradation and prevent co-activation. HIF hydroxylases are part of the 2-oxoglutarate (2-OG)-dependent dioxygenase enzyme family, that require 2-OG and oxygen as substrates and ascorbate and iron as co-factors. The role of ascorbate in regulating the hypoxic pathway in cancer is of interest, with previous research showing reduced HIF pathway activity with increasing tumour ascorbate levels. Brain tissue has one of the highest ascorbate levels in the body, and is one of the last to become depleted under deficiency, indicating an important role for ascorbate in this tissue. One previous study has analysed ascorbate levels in 11 human glioblastoma patients, and showed lower ascorbate in tumour tissue compared to normal brain tissue. There have been no studies investigating the relationship between ascorbate levels and the hypoxic pathway in human glioma tissues. MATERIAL AND METHODS Human glioma tissues (n = 39), obtained from the Cancer Society Tissue Bank Christchurch (ethics approval H19/163), were processed for ascorbate and hypoxic pathway proteins (HIF-1α, CA-IX, BNIP3, HKII, GLUT1 and VEGF). Ascorbate levels were quantified by HPLC-ED, and proteins were measured by Western blotting and ELISA. Spearman’s correlations were used to identify relationships between ascorbate and HIF pathway proteins. RESULTS Of the samples, 64% were GBM. Ascorbate was significantly lower in GBM compared to low-grade gliomas (p = 0.04). VEGF was significantly higher in GBM compared to astrocytomas (p = 0.01). Increased tumour ascorbate was associated with lower VEGF and CA-IX proteins. HIF-1α and BNIP3 protein were positively associated, and VEGF was positively associated with HKII and CA-IX. VEGF inversely associated with BNIP3, and CA-IX inversely associated with HKII. The hypoxic pathway score (calculated from protein levels of members of the hypoxic pathway) was reduced in tumours with higher ascorbate but this did not reach significance (p = 0.2). CONCLUSION This is the first study to show that ascorbate levels were reduced in high-grade gliomas compared to low-grade. Some members of the hypoxic pathway were associated with ascorbate levels. The overall hypoxic pathway score did not significantly correlate with ascorbate and increased numbers of samples are required to confirm any associations. Other variables, such as IDH-1 mutation status of the tumours may affect the correlation and will be analysed next.


2021 ◽  
Author(s):  
Miriam Zatovicova ◽  
Ivana Kajanova ◽  
Monika Barathova ◽  
Martina Takacova ◽  
Martina Labudova ◽  
...  

Abstract Background Hypoxia in the tumor microenvironment (TME) is often the main factor in the cancer progression. Moreover, low levels of oxygen in tumor tissue may signal that the first or second-line therapy will not be successful. This knowledge triggers the inevitable search for different kinds of treatment that will successfully cure aggressive tumors. Due to its exclusive expression on cancer cells, carbonic anhydrase IX belongs to the group of the most precise targets in hypoxic tumors. CA IX possesses several exceptional qualities that predetermine its crucial role in targeted therapy. Its expression on the cell membrane makes it an easily accessible target, while its absence in healthy corresponding tissues makes the treatment practically harmless. The presence of CA IX in solid tumors causes an acidic environment that may lead to the failure of standard therapy. Methods Parental mouse hybridomas (IV/18 and VII/20) were humanized to antibodies which were subsequently named CA9hu-1 and CA9hu-2. From each hybridoma we obtained 25 clones. Each clone was tested for ADCC and CDC activity, affinity, extracellular pH measurement, multicellular aggregation analysis and real-time monitoring of invasion with xCELLigence system. ResultsBoth CA9hu-1 and CA9hu-2 are IgG1 antibodies and they were both examined in vivo. Here we describe anti-CAIX antibodies that can reverse the failure of standard therapy as a result of an acidic environment by modulating the TME. CA9hu-1 is directed at the conformational epitope of the catalytic domain, while CA9hu-2 targets the sequential epitope of the proteo-glycan domain. They are both able to induce an immune response, have high affinity, as well as ADCC and CDC activity. While the first one internalizes after binding to the antigen, the second one is able to reduce metastases formation. More importantly, they have both proved the ability to block the acidification of the extracellular environment. ConclusionCA9hu-1 and CA9hu-2 are the very first humanized antibodies against CA IX that are likely to become suitable therapies for hypoxic tumors. These antibodies can be applied in the treatment therapy of primary tumors and suppression of metastases formation.


2021 ◽  
Vol 22 (16) ◽  
pp. 8808
Author(s):  
Antje Güttler ◽  
Yvonne Eiselt ◽  
Anne Funtan ◽  
Andreas Thiel ◽  
Marina Petrenko ◽  
...  

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.


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