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Cancer Drug Resistance 2021年第2期4卷 343-355页

作者： Kathryn F.Tonissen Sally-Ann Poulsen Griffith Institute for Drug Discovery Griffith UniversityBrisbane 4111Australia School of Environment and Science Griffith UniversityBrisbane 4111Australia.

Intrinsic or acquired resistance to chemotherapy is a major hurdle in the treatment of cancer.One of the key mechanisms of resistance is the overexpression of the drug efflux transporter P-glycoprotein(Pgp).Pgp overexpression renders a large number of mechanistically unrelated chemotherapies ineffective.Targeting Pgp inhibition directly to overcome drug resistance,although conceptually and mechanistically attractive,has not translated to the clinic,in part because Pgp also has a critical protective function in many healthy tissues.It was recently discovered that Carbonic anhydrase XII(CA XII),an enzyme associated with pH regulation in cancer,is co-expressed and co-located with Pgp in drug resistant cancer cells.CA XII is also upregulated by hypoxia,which is another microenvironmental factor that contributes to drug resistance.Here,we review findings that demonstrate modulation of CA XII may offer a promising new approach towards overcoming the longstanding hurdle of drug resistance and therapy failure against solid cancers.This review covers the use of CA XII inhibitors,both small molecule and antibody,in combination with chemotherapeutics that are substrates for Pgp.This combination therapy approach restores the efficacy of chemotherapy in resistant cells and offers a potential new therapeutic window to re-examine the targeting of Pgp as a safe,effective,and novel anticancer strategy.

关键词： Carbonic anhydrase XII P-glycoprotein drug resistance tumor microenvironment pH hypoxia inhibitor chemotherapy

Inhibition of Carbonic anhydrase IX as a novel anticancer mechanism

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World Journal of Clinical Oncology 2012年第7期3卷 98-103页

作者： Claudiu T Supuran Laboratorio di Chimica Bioinorganica University of Florence Polo Scientifico Room 188 Via della Lastruccia 3 50019 Sesto Fiorentino Florence Italy

Carbonic anhydrases(CA, EC 4.***.1.1) catalyze the interconversion bewteen carbon dioxide and bicarbonate with generation of protons. The Carbonic anhydrase isozyme Ⅸ(CA Ⅸ) is highly overexpresed in hypoxic tumors and shows very restricted expression in normal tissues. CA Ⅸ is a dimeric protein possessing very high catalytic activity for the hydration of carbon dioxide to protons and bicarbonate. Its quaternary structure is unique among members of this family of enzymes, allowing for structure-based drug design campaigns of selective inhibitors. Inhibition of CA Ⅸ with sulfonamide and/or coumarin inhibitors was recently shown to lead to a potent retardation for the growth of both primary tumors and metastases. Some fluorescent sulfonamides were shown to accumulate only in hypoxic tumor cells overexpressing CA Ⅸ, and might be used as diagnostic tools for imaging of hypoxic cancers. Sulfonamide inhibitors were also more effective in inhibiting the growth of the primary tumors when associated with irrdiation. CA Ⅸ is thus both a diagnostic and therapeutic validated target for the management of hypoxic tumors normally non-responsive to classical chemio- and radiotherapy.

关键词： Carbonic anhydrase Hypoxia Sulfonamides Coumarins Tumorigenesis Tumor imaging Tumor acidification

Hypoxia and cytokines regulate Carbonic anhydrase 9 expression in hepatocellular carcinoma cells in vitro

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World Journal of Clinical Oncology 2012年第6期3卷 82-91页

作者： Feray Kockar Hatice Yildrim Rahsan Ilikci Sagkan Carsten Hagemann Yasemin Soysal Jelena Anacker Ahmed Ayad Hamza Dirk Vordermark Michael Flentje Harun M Said Department of Biology Faculty of Art and Science Balikesir University Department of Immunology and Allergy Diseases Gulhane Military Medical Academy Tumorbiology Laboratory Department of Neurosurgery University of Würzburg Faculty of Medicine Department of Medical Genetics Afyon Kocatepe University Department of Obstetrics and Gynaecology University of Würzburg School of Medicine Southern Illinois University Department of Radiation Oncology University-Halle-Wittenberg Department of Radiation Oncology University of Wuerzburg

AIM: To study the expression of Carbonic anhydrase(CA) 9 in human hepatocellular carcinoma(HCC) cells.METHODS: We studied CA9 protein, CA9 m RNA and hypoxia-inducible factor-1 alpha(HIF-1α) protein levels in Hep3 B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia(24 h 0.1% O2) without or with interleukin(IL)-1, IL-6, tumor necrosis factoralpha(TNF-α) and transforming growth factor-beta(TGF-β) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation.RESULTS: The tumour cell line analysed showed a strong hypoxic CA9 m RNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1α protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-α and TGF-β, under normoxic conditions significantly increased the Carbonic anhydrase 9 expression level at both the protein and m RNA level, almost doubling the CA9 m RNA and CA9 and HIF-1α protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-α and TGF-β, positively influence CA9 expression under both normoxic and hypoxic conditions.CONCLUSION: These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provideevidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive diseas

关键词： Angiogenesis Carbonic anhydrase 9 Hypoxia Hypoxia-inducible factor-1 alpha Oxygen Radiotherapy Transforming growth factor-beta Tumour microenviroment

Carbonic anhydrase enzymes Ⅱ, Ⅶ, Ⅸ and Ⅻ in colorectal carcinomas

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World Journal of Gastroenterology 2016年第36期22卷 8168-8177页

作者： Pia Viikil? Antti J Kivel? Harri Mustonen Selja Koskensalo Abdul Waheed William S Sly Jaromir Pastorek Silvia Pastorekova Seppo Parkkila Caj Haglund School of Medicine University of Tampere and Fimlab Ltd Tampere University Hospital Department of Surgery University of Helsinki and Helsinki University Hospital Department of Biochemistry and Molecular Biology Saint Louis University School of Medicine Centre of Molecular Medicine Institute of Virology Slovak Academy of Sciences Research Programs Unit Translational Cancer Biology University of Helsinki

AIM To investigate expression of four alpha-Carbonic anhydrases(CAs) in colorectal carcinomas(CRC) and compare the results with patients' survival.METHODS Colorectal carcinoma samples from 539 CRC patients and control tissues were arranged as tissue microarrays and analyzed with antibodies against CA Ⅱ, CA Ⅶ, CA Ⅸ, and CA Ⅻ. Intensity and extent of staining were both scored from 0 to 3 in each sample. These enzyme expression levels were then correlated to patients' survival and clinicopathological parameters, which were tumor differentiation grade and stage, site of tumor, patients' age, and gender. Kaplan-Meier analysis and Cox regression hazard ratio model were used to analyze survival data. RESULTS CA Ⅱ and CA Ⅻ staining intensities correlated with patients' survival in that higher expression indicated poorer prognosis. In Cox regression analysis one unit increase in the CA Ⅱ intensity increased the hazard ratio to 1.19 fold(CI: 1.04-1.37, P = 0.009). A significant correlation was also found when comparing CA Ⅻ staining intensity with survival of CRC patients(HR = 1.18, 95%CI: 1.01-1.38, P = 0.036). The extent of CA Ⅻ immunostaining did not correlate to the patients' survival(P = 0.242, Kaplan-Meier analysis). A significant interaction between age group and extent of the CA Ⅱ staining was found. Increased extent of CA Ⅱ had a significant hazard ratio among patients 65 years and older(1.42, 95%CI: 1.16-1.73, P = 0.0006). No correlations were found between CA Ⅶ(intensity P = 0.566, extent P = 0.495, Kaplan-Meier analysis), or CA Ⅸ(intensity P = 0.879, extent P = 0.315, KaplanMeier analysis) immunostaining results and survival, or the other parameters. CONCLUSION The present findings indicate that CA Ⅱ and CA Ⅻ could be useful in predicting survival in CRC.

关键词： Biomarker Carbonic anhydrase Colorectal cancer Immunohistochemistry Prognosis Survival

Overexpression of Carbonic anhydrase Ⅱ and Ki-67 proteins in prognosis of gastrointestinal stromal tumors

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World Journal of Gastroenterology 2013年第16期19卷 2473-2480页

作者： Li-Cheng Liu Wen-Tong Xu Xin Wu Po Zhao Ya-Li Lv Lin Chen Department of General Surgery General Hospital of PLA Department of Pathology General Hospital of PLA

AIM: To investigate the expression and prognostic value of Carbonic anhydrase Ⅱ (CA Ⅱ) and Ki-67 in gastrointestinal stromal tumors (GISTs). METHODS: One hundred and thirteen GIST patients admitted to Chinese People's Liberation Army General Hospital from January 2004 to December 2010 were retrospectively followed up, and immunohistochemistry was used to detect CA Ⅱ, Ki-67 and CD117 expression in tumor samples. The survival rates of the patients were analyzed using the Kaplan-Meier method. Log-rank test, χ 2 test and Cox proportional hazards model were used to determine the relationships between CA Ⅱ, Ki-67 and CD117 expression and prognostic value in GISTs. RESULTS: The survival rates at 1, 3 and 5 years were 90.0%, 82.0% and 72.0% in all patients. However, in patients with positive CA Ⅱ or Ki-67, the survival rates were 92.0%, 83.0% and 77.0% or 83.0%, 66.6% and 53.0%, respectively. Compared with the negative groups, the survival rates in the positive groups were significantly lower (CA Ⅱ log-rankP = 0.000; Ki-67 logrank P = 0.004). Multivariate Cox analysis revealed that CA Ⅱ, CD117 and Ki-67 were considerable immune factors in prognosis of GIST patients (CA Ⅱ P = 0.043; CD117 P = 0.042; Ki-67 P = 0.007). Besides, tumor diameter, mitotic rate, tumor site, depth of invasion, complete resection, intraoperative rupture, and adjuvant therapy were important prognosis predictive factors. Our study indicated that CA Ⅱ had strong expression in GISTs and the prognosis of GISTs with high CA Ⅱ expression was better than that of GISTs with low or no expression, suggesting that CA Ⅱ is both a diagnostic and prognostic biomarker for GIST. CONCLUSION: CA Ⅱ and Ki-67 are significant prognostic factors for GISTs. CA Ⅱ associated with neovascular endothelia could serve as a potential target for cancer therapy.

关键词： Gastrointestinal stromal tumors Carbonic anhydrase CD117 Ki-67 Prognostic factor

Investigating Catalase and Carbonic Anhydrase Enzyme Activities and Levels of Certain Trace Elements and Heavy Metals in Patients with Primary and Metastatic Hepatic Carcinoma

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Journal of Cancer Therapy 2013年第8期4卷 1373-1381页

作者： Ayse Arslan Halit Demir Harun Arslan Department of Biochemistry Faculty of Science Yuzuncu Yil University Van Turkey Radiology Department Van Regional Training and Research Hospital Van Turkey

Hepatocellular carcinoma (HCC) is among most common terminal cancer types in the world. Primary etiological factors include cirrhosis, hepatitis, aflatoxin and alcohol. The current study was conducted to determine cytosolic erythrocyte Carbonic anhydrase and catalase enzyme activities and levels of some trace elements. For this purpose, 40 patients with primary and metastatic hepatic cancer and 29 healthy volunteers enrolled to the study. Catalase and Carbonic anhydrase enzyme activities and serum trace element levels were measured in patient and control groups. In the current study, serum copper, magnesium, manganese and zinc levels were lower in the primary and metastatic hepatic cancer group in comparison with the control group (P Carbonic anhydrase level was higher in the cancer group (P Carbonic anhydrase enzyme can be a useful indicator in the diagnosis of cancer. However, this issue warrants further investigation.

关键词： Primary and Metastatic Liver Cancer Catalase Carbonic Anhydrase Trace Element Heavy Metal

Malaria parasite Carbonic anhydrase:inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

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Asian Pacific Journal of Tropical Biomedicine 2011年第3期1卷 233-242页

作者： Sudaratana R Krungkrai Jerapan Krungkrai Unit of Biochemistry Department of Medical Science.Faculty of ScienceRangsit University Department of Biochemistry Faculty of MedicineChulalongkorn University

Plasmodium falciparum(P.falciparum) is responsible for the majority of life-threatening cases of human malaria,causing 1.5-2.7 million annual deaths.The global emergence of drug-resistant malaria parasites necessitates identification and characterisation of novel drug targets and their potential inhibitors.We identified the Carbonic anhydrase(CA) genes in P.falciparum.The pfGA gene encodes an α-Carbonic anhydrase,a Zn^(2+)-metalloenzme,possessing catalytic properties distinct from that of the human host CA enzyme.The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes.A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions.The structure of the groups substituting the aromatic-ureido-or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides.One derivative,that is,4-(3,4-dichlorophenylureido)thioureidobcnzcnesulfonamide(compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor,and was also the most effective antimalarial compound on the in vitro P.falciparum growth inhibition.The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei,an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.

关键词： Malaria Plasmodium falciparum Carbonic anhydrase Carbonic anhydrase inhibitor Aromalic/heterocyclic sulfonamides Antimalarial agents Drug target Parasitic disease

Relationship among Photosys-tem Ⅱ Carbonic anhydrase,extrinsic polypeptides and manganese cluster

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Chinese Science Bulletin 2001年第5期46卷 406-409页

作者： DAI Xinbin YU Yong ZHANG Rongxian YU Xinjian HE Peiming XU Chunhe Nanjing Agricultural University Agronomy DepartmentNanjing 210095China Shanghai Institute of Plant Physiology Chinese Academy of SciencesShanghai 200032China

Effects of Photosystem Ⅱ (PS Ⅱ) extrinsic polypeptides of oxygen-evolving complex and manganese clusters on PS Ⅱ Carbonic anhydrase (CA) were studied with spinach PS Ⅱ membranes. The result supported that membrane-bound CA is located in the donor side of PS Ⅱ. The extrinsic polypeptides played an important role of maintaining CA activity. After removing manganese clusters, oxygen evolution activity was inhibited, but PSⅡ-CA activity was unchanged. It was concluded that CA activity is independent of the presence of manganese clusters, and was not directly correlated with oxygen evolution activity.

关键词： Carbonic anhydrase PS II oxygen evolution complex extrinsic polypeptide manganese cluster.

Screening and docking studies of natural phenolic inhibitors of Carbonic anhydrase Ⅱ

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Science China Chemistry 2009年第3期52卷 332-337页

作者： HUANG HuoQiang1, 2, PAN XuLin1, JI ChangJiu1, 2, ZENG GuangZhi1, JIANG LiHua1, FU Xiang1, LIU JiKai1, HAO XiaoJiang1, ZHANG YingJun1 & TAN NingHua1 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China 2 Graduate University of the Chinese Academy of Sciences, Beijing 100049, China State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of Botany Chinese Academy of Sciences Kunming China Graduate University of the Chinese Academy of Sciences Beijing China

Carbonic anhydrase Ⅱ (CAⅡ) is an important enzyme complex with Zn2+,which is involved in many physiological and pathological processes, such as calcification, glaucoma and tumorigenicity. In order to search for novel inhibitors of CAⅡ, inhibition assay of Carbonic anhydrase Ⅱ was performed, by which seven natural phenolic compounds, including four phenolics (grifolin, 4-O-methyl-grifolic acid, grifolic acid, and isovanillic acid) and three flavones (eriodictyol, quercetin and puerin A), showed in-hibitory activities against CAⅡ with IC50s in the range of 6.37-71.73 μmol/L. Grifolic acid is the most active one with IC50 of 6.37 μmol/L. These seven phenolic compounds were proved to be novel natural Carbonic anhydrase Ⅱ inhibitors, which were obtained in flexible docking study with GOLD 3.0 soft-ware. Results indicated that the aliphatic chain and polar groups of hydroxyl and carboxyl are impor-tant to their inhibitory activities, providing a new insight into study on CA Ⅱ potent inhibitors.

关键词： Carbonic anhydraseⅡ natural inhibitors screening docking

Thermodynamic study on conformation change of Carbonic anhydrase

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Chinese Science Bulletin 1998年第21期43卷 1802-1805页

作者： Yunna Liu Buxing Han Fu Tan Chinese Acad Sci Inst Chem Beijing 100080 Peoples R China

The effect of pHs on structural stability of the zinc-containing metalloenzyme Carbonic anhydrase has been studied by means of differential scanning calorimetry. The rule of the conformational change for the enzyme with pH change has been found by thermodynamic analysis. The experimental results also provide valuable information: in the pH range from 5.26 to 9.04, two independent endothermal peaks were observed on DSC thermogram. It shows the existence of two structural domains in the molecule. The transition temperature and enthalpy of the two domains are different.

关键词： Carbonic anhydrase conformation change DSC thermodynamics