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Saravanan V, Palani SP, Chagaleti BK, Gao QZ, Valsaladevi AG, Kumaradoss KM. Molecular dynamics simulation reveals structural insights into isozyme selectivity of carbonic anhydrase XII inhibitors in hypoxic tumor microenvironment. Biochem Biophys Res Commun 2025; 753:151471. [PMID: 39965264 DOI: 10.1016/j.bbrc.2025.151471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/23/2024] [Accepted: 02/08/2025] [Indexed: 02/20/2025]
Abstract
Human carbonic anhydrase (CA) isoenzymes IX and XII are overexpressed in cancer cells, contributing to tumor microenvironment acidification and representing important targets for cancer therapy. In this study, we identified compound V35 (ZINC09419065) as a selective inhibitor of CA IX and CA XII with enhanced binding stability and selectivity compared to standard inhibitors. We analyzed conserved regions in CA I, CA II, CA IX, and CA XII to investigate their isozyme selectivity, revealing critical selectivity determinants at positions 95, 141, and 203. Molecular docking results indicated that V35 interacts robustly with CA XII, forming a metal ion coordination complex with Zn via HIS94, HIS96, HIS119, and THR199, similar to the interaction pattern of standard inhibitor SLC-0111. Molecular dynamics (MD) simulations conducted over 500 ns under hypoxic conditions showed that V35 has high binding stability, with root mean square deviation (RMSD) and fluctuation (RMSF) values comparable to SLC-0111, demonstrating its conformational stability in CA XII. Binding free energy calculations using the MMGBSA method showed that V35 achieves binding free energy of -44.17 kcal/mol with CA XII, closely matching SLC-0111 (-49.41 kcal/mol). Density functional theory (DFT) calculations further highlighted V35's electrostatic potential distribution, supporting its isozyme selectivity. Post-dynamics analysis indicated that the ester functional groups and the inward movement of HIS64 stabilize V35's interactions in CA XII, a feature absent in CA I.
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Affiliation(s)
- Venkatesan Saravanan
- Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, India
| | - Sathiya Priya Palani
- Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, India
| | - Bharath Kumar Chagaleti
- Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, India
| | - Quan-Ze Gao
- National Applied Research Laboratories, National Centre for High-Performance Computing, Hsinchu City, 30076, Taiwan
| | - Anjana Gopi Valsaladevi
- Dr APJ Abdul Kalam Lab, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, India.
| | - Kathiravan Muthu Kumaradoss
- Dr APJ Abdul Kalam Lab, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, 603203, India.
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2
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Lee HY, Elkamhawy A, Al-Karmalawy AA, Nada H, Giovannuzzi S, Supuran CT, Lee K. Chalcone-based benzenesulfonamides as potent and selective inhibitors for human carbonic anhydrase II: Design, synthesis, in vitro, and in silico studies. Arch Pharm (Weinheim) 2024; 357:e2400069. [PMID: 39240035 DOI: 10.1002/ardp.202400069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 08/06/2024] [Accepted: 08/16/2024] [Indexed: 09/07/2024]
Abstract
Sulfonamides are promising classical carbonic anhydrase (CA; EC 4.2.1.1) inhibitors, being used for several medical purposes such as diuretics, anticonvulsants, topically acting antiglaucoma agents, for antiobesity and anticancer therapies. Herein, a series of chalcone-based benzenesulfonamides (3a‒m) was synthesized and assessed for its inhibitory activity against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX, and XII). Most compounds displayed single- to double-digit nanomolar inhibition constants (Kis), with some derivatives being more potent and/or selective than the standard drug acetazolamide (AAZ). Among the synthesized compounds, 3g compound demonstrated the highest inhibitory activity against the hCA II isoform (Ki = 2.5 nM) with 30-, 9-, and 11-fold selectivity for hCA II over the I, IX, and XII isoforms, respectively. Structure-activity relationships for different substitution patterns were analyzed. Additionally, a molecular docking study showed that compound 3g bound to hCA II by coordinating with the zinc ion through the deprotonated benzenesulfonamide moiety, in addition to a hydrogen bond formed between an oxygen of the sulfonamide moiety and Thr199. Moreover, the chalcone core participated in van der Waals interactions with some active site residues, such as Ile91, Val121, and Leu198. Consequently, this report introduces a successful approach toward identifying compound 3g as a highly potent and selective chalcone-based benzenesulfonamide inhibitor of hCA II worthy of further investigation.
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Affiliation(s)
- Hwa Young Lee
- BK21 FOUR Team and Integrated Research, Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
| | - Ahmed Elkamhawy
- Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Astana, Kazakhstan
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, Egypt
| | - Hossam Nada
- BK21 FOUR Team and Integrated Research, Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
| | - Simone Giovannuzzi
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy
| | - Claudiu T Supuran
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy
| | - Kyeong Lee
- BK21 FOUR Team and Integrated Research, Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
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3
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Bua S, Nocentini A, Bonardi A, Palma G, Ciampi G, Giliberti A, Iannelli F, Bruzzese F, Supuran CT, de Nigris F. Harnessing Nitric Oxide-Donating Benzofuroxans for Targeted Inhibition of Carbonic Anhydrase IX in Cancer. J Med Chem 2024; 67:15892-15907. [PMID: 39207927 DOI: 10.1021/acs.jmedchem.4c01563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28, demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.
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Affiliation(s)
- Silvia Bua
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Alessio Nocentini
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Alessandro Bonardi
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Giuseppe Palma
- Experimental Animal Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli 80131, Italy
| | - Giulia Ciampi
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli″, Napoli 80138, Italy
| | - Angela Giliberti
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli″, Napoli 80138, Italy
| | - Federica Iannelli
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS -Fondazione G. Pascale, Napoli 80131, Italy
| | - Francesca Bruzzese
- Experimental Animal Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli 80131, Italy
| | - Claudiu T Supuran
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Filomena de Nigris
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli″, Napoli 80138, Italy
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4
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Masci D, Puxeddu M, Di Magno L, D’Ambrosio M, Parisi A, Nalli M, Bai R, Coluccia A, Sciò P, Orlando V, D’Angelo S, Biagioni S, Urbani A, Hamel E, Nocentini A, Filiberti S, Turati M, Ronca R, Kopecka J, Riganti C, Fionda C, Bordone R, Della Rocca G, Canettieri G, Supuran CT, Silvestri R, La Regina G. 4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1 H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells. J Med Chem 2023; 66:14824-14842. [PMID: 37902628 PMCID: PMC10641813 DOI: 10.1021/acs.jmedchem.3c01424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/31/2023]
Abstract
We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/β-catenin signaling pathway. The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 (Ki = 6.8 nM) suppressed the Wnt/β-catenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved caspase-3. Compound 15 showed strong inhibition of viability in a panel of cancer cells, including colorectal cancer and triple-negative breast cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15 is a novel dual-targeting compound with activity against hCA and Wnt/β-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.
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Affiliation(s)
- Domiziana Masci
- Department
of Basic Biotechnological Sciences, Intensivological and Perioperative
Clinics, Catholic University of the Sacred
Heart, Largo Francesco
Vito 1, Rome 00168, Italy
| | - Michela Puxeddu
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Laura Di Magno
- Laboratory
Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti,
Department of Molecular Medicine, Sapienza
University of Rome, Viale
Regina Elena 291, Rome 00161, Italy
| | - Michele D’Ambrosio
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Anastasia Parisi
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Marianna Nalli
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Ruoli Bai
- Molecular
Pharmacology Branch, Developmental Therapeutics Program, Division
of Cancer Treatment and Diagnosis, Frederick National Laboratory for
Cancer Research, National Cancer Institute,
National Institutes of Health, Frederick, Maryland 21702, United States
| | - Antonio Coluccia
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Pietro Sciò
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Viviana Orlando
- Department
of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy
| | - Sara D’Angelo
- Department
of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy
| | - Stefano Biagioni
- Department
of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy
| | - Andrea Urbani
- Department
of Basic Biotechnological Sciences, Intensivological and Perioperative
Clinics, Catholic University of the Sacred
Heart, Largo Francesco
Vito 1, Rome 00168, Italy
| | - Ernest Hamel
- Molecular
Pharmacology Branch, Developmental Therapeutics Program, Division
of Cancer Treatment and Diagnosis, Frederick National Laboratory for
Cancer Research, National Cancer Institute,
National Institutes of Health, Frederick, Maryland 21702, United States
| | - Alessio Nocentini
- Dipartimento
Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universitá degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino I-50019, Firenze, Italy
| | - Serena Filiberti
- Experimental
Oncology and Immunology Unit, Department of Molecular and Translational
Medicine, University of Brescia, Via Branze 39, Brescia 25123, Italy
| | - Marta Turati
- Experimental
Oncology and Immunology Unit, Department of Molecular and Translational
Medicine, University of Brescia, Via Branze 39, Brescia 25123, Italy
| | - Roberto Ronca
- Experimental
Oncology and Immunology Unit, Department of Molecular and Translational
Medicine, University of Brescia, Via Branze 39, Brescia 25123, Italy
| | - Joanna Kopecka
- Department
of Oncology and Molecular Biotecnology Center “Guido Tarone″, Oncological Pharmacology Unit, Via Nizza 44, Torino 10126, Italy
| | - Chiara Riganti
- Department
of Oncology and Molecular Biotecnology Center “Guido Tarone″, Oncological Pharmacology Unit, Via Nizza 44, Torino 10126, Italy
| | - Cinzia Fionda
- Laboratory
Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti,
Department of Molecular Medicine, Sapienza
University of Rome, Viale
Regina Elena 291, Rome 00161, Italy
| | - Rosa Bordone
- Laboratory
Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti,
Department of Molecular Medicine, Sapienza
University of Rome, Viale
Regina Elena 291, Rome 00161, Italy
| | - Giorgia Della Rocca
- Laboratory
Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti,
Department of Molecular Medicine, Sapienza
University of Rome, Viale
Regina Elena 291, Rome 00161, Italy
| | - Gianluca Canettieri
- Laboratory
Affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti,
Department of Molecular Medicine, Sapienza
University of Rome, Viale
Regina Elena 291, Rome 00161, Italy
| | - Claudiu T. Supuran
- Dipartimento
Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universitá degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino I-50019, Firenze, Italy
| | - Romano Silvestri
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
| | - Giuseppe La Regina
- Laboratory
Affiliated with the Institute Pasteur Italy—Cenci Bolognetti
Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Roma 00185, Italy
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5
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Chen HY, Lin CE, Wu SC, Yang ZY, Chiang YF, Huang KC, Wang KL, Ali M, Shieh TM, Chang HY, Huang TC, Hsia SM. Para-toluenesulfonamide, a novel potent carbonic anhydrase inhibitor, improves hypoxia-induced metastatic breast cancer cell viability and prevents resistance to αPD-1 therapy in triple-negative breast cancer. Biomed Pharmacother 2023; 167:115533. [PMID: 37748406 DOI: 10.1016/j.biopha.2023.115533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/10/2023] [Accepted: 09/17/2023] [Indexed: 09/27/2023] Open
Abstract
Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl2), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl2-induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer.
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Affiliation(s)
- Hsin-Yuan Chen
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Chia-En Lin
- Gongwin Biopharm Co., Ltd., Taipei 104001, Taiwan
| | - Shun-Chi Wu
- Gongwin Biopharm Co., Ltd., Taipei 104001, Taiwan
| | - Zong-Yu Yang
- Gongwin Biopharm Co., Ltd., Taipei 104001, Taiwan
| | - Yi-Fen Chiang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Ko-Chieh Huang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Kai-Lee Wang
- Department of Nursing, Deh Yu College of Nursing and Health, Keelung 20301, Taiwan
| | - Mohamed Ali
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, 11566 Cairo, Egypt
| | - Tzong-Ming Shieh
- School of Dentistry, College of Dentistry, China Medical University, Taichung 40402, Taiwan
| | - Hsin-Yi Chang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Tsui-Chin Huang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
| | - Shih-Min Hsia
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; School of Food Safety, Taipei Medical University, Taipei 11031, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan; TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110301, Taiwan.
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6
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Development of potent nanosized carbonic anhydrase inhibitor for targeted therapy of hypoxic solid tumors. Int J Pharm 2023; 631:122537. [PMID: 36572260 DOI: 10.1016/j.ijpharm.2022.122537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
Overexpression of two carbonic anhydrase (CA) isoforms, CA IX and XII, in several hypoxic solid tumors provides an extracellular hypoxic microenvironment, interferes with extra- and intracellular pH regulation, thus favoring hypoxic tumor cell survival, proliferation and metastasis. In the current study, a selective inhibitor for human CA isoforms IX and XII (isatin-bearing sulfonamide, WEG-104), was incorporated into nanosized spherical niosomes at high encapsulation efficiency to allow for an enhanced and sustained antitumor activity. In vivo, administration of WEG-104 that is either free (10 mg/kg) or loaded into niosomes (5 mg/kg) into a mice model of Ehrlich ascites solid tumor resulted in comparable efficacy in terms of reduction of tumor weight and volume. Administration of WEG-104-loaded niosomes (10 mg/kg) exhibited superior antitumor activity compared to the free drug, evidenced by reduced tumor weight and volume, marked reduction in the activity of CA IX and XII, and suppression of HIF-1α and MMP-2. Moreover, prominent increase of caspase 3 and pronounced decrease in VEGF immune expression were observed in the treated animals. Hence, loading of molecularly designed compounds that targets CAs in hypoxic solid tumors into nanosized delivery systems provided an auspicious strategy for limiting solid tumor progression and malignancy.
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7
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Shahin AI, Zaraei SO, AlKubaisi BO, Ullah S, Anbar HS, El-Gamal R, Menon V, Abdel-Maksoud MS, Oh CH, El-Awady R, Gelsleichter NE, Pelletier J, Sévigny J, Iqbal J, Al-Tel TH, El-Gamal MI. Design and synthesis of new adamantyl derivatives as promising antiproliferative agents. Eur J Med Chem 2023; 246:114958. [PMID: 36470105 DOI: 10.1016/j.ejmech.2022.114958] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/19/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Abstract
A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC50 values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC50 value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes.
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Affiliation(s)
- Afnan I Shahin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Seyed-Omar Zaraei
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Bilal O AlKubaisi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Saif Ullah
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan
| | - Hanan S Anbar
- Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates
| | - Randa El-Gamal
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Varsha Menon
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Mohammed S Abdel-Maksoud
- Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre NRC (ID: 60014618), Dokki, Giza, 12622, Egypt
| | - Chang-Hyun Oh
- Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon, 305-333, Republic of Korea
| | - Raafat El-Awady
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Nicolly Espindola Gelsleichter
- Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada; Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada
| | - Julie Pelletier
- Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada
| | - Jean Sévigny
- Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada; Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada
| | - Jamshed Iqbal
- Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
| | - Taleb H Al-Tel
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
| | - Mohammed I El-Gamal
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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8
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Lin FL, Yen JT, Fang PW, Xu SQ, Lin JC, Tan KT. Protein-Labeling Fluorescent Probe Reveals Ectodomain Shedding of Transmembrane Carbonic Anhydrases. ACS Chem Biol 2022; 17:3218-3228. [PMID: 36318872 DOI: 10.1021/acschembio.2c00679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
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. Using both chemical and genetic approaches, we identified that the ADAM17 metalloprotease is responsible for the shedding of carbonic anhydrases. Compared to current immunological methods, this protein-labeling approach not only detects ectodomain released into the culture media but also allows real-time living cell tracking and quantitative analysis of remnant proteins on the cell surface, thereby providing a more detailed insight into the mechanism of ectodomain shedding as well as protein lifetime on the cell surface.
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Affiliation(s)
- Fang-Ling Lin
- Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China
| | - Jui-Ting Yen
- Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China
| | - Pin-Wen Fang
- Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China
| | - Shun-Qiang Xu
- Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China
| | - Jing-Cyun Lin
- Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China
| | - Kui-Thong Tan
- Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China.,Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan Republic of China.,Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan Republic of China
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9
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Chalcogen Bond as a Factor Stabilizing Ligand Conformation in the Binding Pocket of Carbonic Anhydrase IX Receptor Mimic. Int J Mol Sci 2022; 23:ijms232213701. [PMID: 36430173 PMCID: PMC9691181 DOI: 10.3390/ijms232213701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/24/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
It is postulated that the overexpression of Carbonic Anhydrase isozyme IX in some cancers contributes to the acidification of the extracellular matrix. It was proved that this promotes the growth and metastasis of the tumor. These observations have made Carbonic Anhydrase IX an attractive drug target. In the light of the findings and importance of the glycoprotein in the cancer treatment, we have employed quantum-chemical approaches to study non-covalent interactions in the binding pocket. As a ligand, the acetazolamide (AZM) molecule was chosen, being known as a potential inhibitor exhibiting anticancer properties. First-Principles Molecular Dynamics was performed to study the chalcogen and other non-covalent interactions in the AZM ligand and its complexes with amino acids forming the binding site. Based on Density Functional Theory (DFT) and post-Hartree-Fock methods, the metric and electronic structure parameters were described. The Non-Covalent Interaction (NCI) index and Atoms in Molecules (AIM) methods were applied for qualitative/quantitative analyses of the non-covalent interactions. Finally, the AZM-binding pocket interaction energy decomposition was carried out. Chalcogen bonding in the AZM molecule is an important factor stabilizing the preferred conformation. Free energy mapping via metadynamics and Path Integral molecular dynamics confirmed the significance of the chalcogen bond in structuring the conformational flexibility of the systems. The developed models are useful in the design of new inhibitors with desired pharmacological properties.
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10
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Queen A, Bhutto HN, Yousuf M, Syed MA, Hassan MI. Carbonic anhydrase IX: A tumor acidification switch in heterogeneity and chemokine regulation. Semin Cancer Biol 2022; 86:899-913. [PMID: 34998944 DOI: 10.1016/j.semcancer.2022.01.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/30/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
Abstract
The primary physiological process of respiration produces carbon dioxide (CO2) that reacts with water molecules which subsequently liberates bicarbonate (HCO-3) and protons. Carbonic anhydrases (CAs) are the primary catalyst involved in this conversion. More than 16 isoforms of human CAs show organ or subcellular specific activity. Dysregulation of each CA is associated with multiple pathologies. Out of these members, the overexpression of membrane-bound carbonic anhydrase IX (CAIX) is associated explicitly with hypoxic tumors or various solid cancers. CAIX helps tumors deal with higher CO2 by sequestering it with bicarbonate ions and helping cancer cells to grow in a comparatively hypoxic or acidic environment, thus acting as a pH adaptation switch. CAIX-mediated adaptations in cancer cells include angiogenesis, metabolic alterations, tumor heterogeneity, drug resistance, and regulation of cancer-specific chemokines. This review comprehensively collects and describe the cancer-specific expression mechanism and role of CAIX in cancer growth, progression, heterogeneity, and its structural insight to develop future combinatorial targeted cancer therapies.
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Affiliation(s)
- Aarfa Queen
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Humaira Naaz Bhutto
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mohd Yousuf
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mansoor Ali Syed
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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11
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Rasool A, Batool Z, Khan M, Halim SA, Shafiq Z, Temirak A, Salem MA, Ali TE, Khan A, Al-Harrasi A. Bis-pharmacophore of cinnamaldehyde-clubbed thiosemicarbazones as potent carbonic anhydrase-II inhibitors. Sci Rep 2022; 12:16095. [PMID: 36167735 PMCID: PMC9515202 DOI: 10.1038/s41598-022-19975-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022] Open
Abstract
Here, we report the synthesis, carbonic anhydrase-II (CA-II) inhibition and structure–activity relationship studies of cinnamaldehyde-clubbed thiosemicarbazones derivatives. The derivatives showed potent activities in the range of 10.3 ± 0.62–46.6 ± 0.62 µM. Among all the synthesized derivatives, compound 3n (IC50 = 10.3 ± 0.62 µM), 3g (IC50 = 12.1 ± 1.01 µM), and 3h (IC50 = 13.4 ± 0.52 µM) showed higher inhibitory activity as compared to the standard inhibitor, acetazolamide. Furthermore, molecular docking of all the active compounds was carried out to predict their behavior of molecular binding. The docking results indicate that the most active hit (3n) specifically mediate ionic interaction with the Zn ion in the active site of CA-II. Furthermore, the The199 and Thr200 support the binding of thiosemicarbazide moiety of 3n, while Gln 92 supports the interactions of all the compounds by hydrogen bonding. In addition to Gln92, few other residues including Asn62, Asn67, The199, and Thr200 play important role in the stabilization of these molecules in the active site by specifically providing H-bonds to the thiosemicarbazide moiety of compounds. The docking score of active hits are found in range of − 6.75 to − 4.42 kcal/mol, which indicates that the computational prediction correlates well with the in vitro results.
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Affiliation(s)
- Asif Rasool
- Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan
| | - Zahra Batool
- Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan
| | - Majid Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman
| | - Zahid Shafiq
- Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, 60800, Pakistan. .,Department of Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
| | - Ahmed Temirak
- National Research Centre, Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, Dokki, P.O. Box 12622, Cairo, Egypt
| | - Mohamed A Salem
- Department of Chemistry, Faculty of Science and Arts, King Khalid University, Muhayil, Assir, Saudi Arabia.,Department of Chemistry, Faculty of Science, Al-Azhar University, 11284 Nasr City, Cairo, Egypt
| | - Tarik E Ali
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia.,Department of Chemistry, Faculty of Education, Ain Shams University, Cairo, Egypt
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman.
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Sultanate of Oman.
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12
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Abd Al Moaty MN, El Ashry ESH, Awad LF, Ibrahim NA, Abu-Serie MM, Barakat A, Altowyan MS, Teleb M. Enhancing the Anticancer Potential of Targeting Tumor-Associated Metalloenzymes via VEGFR Inhibition by New Triazolo[4,3-a]pyrimidinone Acyclo C-Nucleosides Multitarget Agents. Molecules 2022; 27:molecules27082422. [PMID: 35458618 PMCID: PMC9026109 DOI: 10.3390/molecules27082422] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/18/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
The role of metalloenzymes in tumor progression had broadened their application in cancer therapy. Of these, MMPs and CAs are validated druggable targets that share some pivotal signaling pathways. The majority of MMPs or CAs inhibitors are designed as single-target agents. Despite their transient efficacy, these agents are often susceptible to resistance. This set the stage to introduce dual inhibitors of correlated MMPs and CAs. The next step is expected to target the common vital signaling nodes as well. In this regard, VEGFR-2 is central to various tumorigenesis events involving both families, especially MMP-2 and CA II. Herein, we report simultaneous inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed hybrid 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides. The promising derivatives were nanomolar inhibitors of VEGFR-2 (8; IC50 = 5.89 nM, 9; IC50 = 10.52 nM) and MMP-2 (8; IC50 = 17.44 nM, 9; IC50 = 30.93 nM) and submicromolar inhibitors of CA II (8; IC50 = 0.21 µM, 9; IC50 = 0.36 µM). Docking studies predicted their binding modes into the enzyme active sites and the structural determinants of activity regarding substitution and regioselectivity. MTT assay demonstrated that both compounds were 12 folds safer than doxorubicin with superior anticancer activities against three human cancers recording single-digit nanomolar IC50, thus echoing their enzymatic activities. Up to our knowledge, this study introduces the first in class triazolopyrimidinone acyclo C-nucleosides VEGFR-2/MMP-2/CA II inhibitors that deserve further investigation.
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Affiliation(s)
- Mohamed Nabil Abd Al Moaty
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (M.N.A.A.M.); (E.S.H.E.A.); (N.A.I.)
| | - El Sayed Helmy El Ashry
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (M.N.A.A.M.); (E.S.H.E.A.); (N.A.I.)
| | - Laila Fathy Awad
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (M.N.A.A.M.); (E.S.H.E.A.); (N.A.I.)
- Correspondence: (L.F.A.); (A.B.)
| | - Nihal Ahmed Ibrahim
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (M.N.A.A.M.); (E.S.H.E.A.); (N.A.I.)
| | - Marwa Muhammad Abu-Serie
- Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt;
| | - Assem Barakat
- Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
- Correspondence: (L.F.A.); (A.B.)
| | - Mezna Saleh Altowyan
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Mohamed Teleb
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;
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13
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Targeting the interplay between MMP-2, CA II and VEGFR-2 via new sulfonamide-tethered isomeric triazole hybrids; Microwave-assisted synthesis, computational studies and evaluation. Bioorg Chem 2022; 124:105816. [DOI: 10.1016/j.bioorg.2022.105816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 12/20/2022]
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14
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Aspatwar A, Tolvanen MEE, Barker H, Syrjänen L, Valanne S, Purmonen S, Waheed A, Sly WS, Parkkila S. Carbonic Anhydrases in Metazoan Model Organisms: Molecules, Mechanisms, and Physiology. Physiol Rev 2022; 102:1327-1383. [PMID: 35166161 DOI: 10.1152/physrev.00018.2021] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
During the past three decades, mice, zebrafish, fruit flies, and Caenorhabditis elegans have been the primary model organisms used for the study of various biological phenomena. These models have also been adopted and developed to investigate the physiological roles of carbonic anhydrases (CAs) and carbonic anhydrase-related proteins (CARPs). These proteins belong to eight CA families and are identified by Greek letters: α, β, γ, δ, ζ, η, θ, and ι. Studies using model organisms have focused on two CA families, α-CAs and β-CAs, which are expressed in both prokaryotic and eukaryotic organisms with species-specific distribution patterns and unique functions. This review covers the biological roles of CAs and CARPs in light of investigations performed in model organisms. Functional studies demonstrate that CAs are not only linked to the regulation of pH homeostasis, the classical role of CAs but also contribute to a plethora of previously undescribed functions.
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Affiliation(s)
- Ashok Aspatwar
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Harlan Barker
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Fimlab Ltd and TAYS Cancer Centre, Tampere University Hospital, Tampere, Finland
| | - Leo Syrjänen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Otorhinolaryngology, Tampere University Hospital, Tampere, Finland
| | - Susanna Valanne
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Sami Purmonen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Abdul Waheed
- Department of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - William S Sly
- Department of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Seppo Parkkila
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Fimlab Ltd and TAYS Cancer Centre, Tampere University Hospital, Tampere, Finland
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15
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Rafiq K, Ur Rehman N, Halim SA, Khan M, Khan A, Al-Harrasi A. Design, Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors. Molecules 2022; 27:molecules27030816. [PMID: 35164091 PMCID: PMC8838037 DOI: 10.3390/molecules27030816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 11/16/2022] Open
Abstract
Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a-l), characterized by 1H- and 13C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a-l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC50 value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.
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Affiliation(s)
- Kashif Rafiq
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman; (K.R.); (S.A.H.); (M.K.); (A.K.)
- Department of Chemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
| | - Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman; (K.R.); (S.A.H.); (M.K.); (A.K.)
- Correspondence: (N.U.R.); (A.A.-H.); Tel.: +968-2544-6328 (A.A.-H.); Fax: +968-2544-6612 (A.A.-H.)
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman; (K.R.); (S.A.H.); (M.K.); (A.K.)
| | - Majid Khan
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman; (K.R.); (S.A.H.); (M.K.); (A.K.)
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman; (K.R.); (S.A.H.); (M.K.); (A.K.)
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Birkat Al Mauz, Nizwa 616, Oman; (K.R.); (S.A.H.); (M.K.); (A.K.)
- Correspondence: (N.U.R.); (A.A.-H.); Tel.: +968-2544-6328 (A.A.-H.); Fax: +968-2544-6612 (A.A.-H.)
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16
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Mussi S, Rezzola S, Chiodelli P, Nocentini A, Supuran CT, Ronca R. Antiproliferative effects of sulphonamide carbonic anhydrase inhibitors C18, SLC-0111 and acetazolamide on bladder, glioblastoma and pancreatic cancer cell lines. J Enzyme Inhib Med Chem 2021; 37:280-286. [PMID: 34894950 PMCID: PMC8667884 DOI: 10.1080/14756366.2021.2004592] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Carbonic anhydrase IX/XII (CA IX/XII), are cell-surface enzymes typically expressed by cancer cells as a form of adaptation to hypoxia and acidosis. It has been widely reported that these proteins play pivotal roles in cancer progression fostering cell migration, aggressiveness and resistance to first line chemo- and radiotherapies. CA IX has emerged as a promising target in cancer therapy and several approaches and families of compounds were characterised in the attempt to find optimal targeting by inhibiting of the high catalytic activity of the enzyme. In the present work, different cell lines representing glioblastoma, bladder and pancreatic cancer have been exploited to compare the inhibitory and antiproliferative effect of primary sulphonamide acetazolamide (AAZ), the Phase Ib/II clinical grade sulphonamide SLC-0111, and a membrane-impermeant positively charged, pyridinium-derivative (C18). New hints regarding the possibility to exploit CA inhibitors in these cancer types are proposed.
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Affiliation(s)
- Silvia Mussi
- Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Sara Rezzola
- Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Paola Chiodelli
- Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Alessio Nocentini
- NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Sesto Fiorentino, Florence, Italy
| | - Claudiu T Supuran
- NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Sesto Fiorentino, Florence, Italy
| | - Roberto Ronca
- Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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17
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Bade RM, Schehr JL, Emamekhoo H, Gibbs BK, Rodems TS, Mannino MC, Desotelle JA, Heninger E, Stahlfeld CN, Sperger JM, Singh A, Wolfe SK, Niles DJ, Arafat W, Steinharter JA, Jason Abel E, Beebe DJ, Wei XX, McKay RR, Choueri TK, Lang JM. Development and initial clinical testing of a multiplexed circulating tumor cell assay in patients with clear cell renal cell carcinoma. Mol Oncol 2021; 15:2330-2344. [PMID: 33604999 PMCID: PMC8410529 DOI: 10.1002/1878-0261.12931] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 12/31/2020] [Accepted: 02/07/2021] [Indexed: 12/21/2022] Open
Abstract
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. Distinct subtypes of ccRCC CTCs were evaluated for PD-L1 and HLA-I expression and correlated with patient response to therapy. CTC enumeration and expression of PD-L1 and HLA-I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker.
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Affiliation(s)
- Rory M. Bade
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
| | | | | | | | | | | | | | - Erika Heninger
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
| | | | - Jamie M. Sperger
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
- Department of MedicineUniversity of Wisconsin‐MadisonWIUSA
| | - Anupama Singh
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
| | | | - David J. Niles
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonWIUSA
| | - Waddah Arafat
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
- Department of MedicineUniversity of Wisconsin‐MadisonWIUSA
| | - John A. Steinharter
- Lank Center for Genitourinary OncologyDana‐Farber Cancer InstituteHarvard UniversityBostonMAUSA
| | - E. Jason Abel
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
- Department of MedicineUniversity of Wisconsin‐MadisonWIUSA
| | - David J. Beebe
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonWIUSA
| | - Xiao X. Wei
- Lank Center for Genitourinary OncologyDana‐Farber Cancer InstituteHarvard UniversityBostonMAUSA
| | - Rana R. McKay
- Lank Center for Genitourinary OncologyDana‐Farber Cancer InstituteHarvard UniversityBostonMAUSA
- Moores Cancer CenterUniversity of California San DiegoLa JollaCAUSA
| | - Toni K. Choueri
- Lank Center for Genitourinary OncologyDana‐Farber Cancer InstituteHarvard UniversityBostonMAUSA
| | - Joshua M. Lang
- Carbone Cancer CenterUniversity of Wisconsin‐MadisonWIUSA
- Department of MedicineUniversity of Wisconsin‐MadisonWIUSA
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18
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The Carbonic Anhydrase Inhibitor E7070 Sensitizes Glioblastoma Cells to Radio- and Chemotherapy and Reduces Tumor Growth. Mol Neurobiol 2021; 58:4520-4534. [PMID: 34085182 DOI: 10.1007/s12035-021-02437-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/18/2021] [Indexed: 01/13/2023]
Abstract
Glioblastomas (GBMs), the most common and lethal primary brain tumor, show inherent infiltrative nature and high molecular heterogeneity that make complete surgical resection unfeasible and unresponsive to conventional adjuvant therapy. Due to their fast growth rate even under hypoxic and acidic conditions, GBM cells can conserve the intracellular pH at physiological range by overexpressing membrane-bound carbonic anhydrases (CAs). The synthetic sulfonamide E7070 is a potent inhibitor of CAs that harbors putative anticancer properties; however, this drug has still not been tested in GBMs. The present study aimed to evaluate the effects of E7070 on CA9 and CA12 enzymes in GBM cells as well as in the tumor cell growth, migration, invasion, and resistance to radiotherapy and chemotherapy. We found that E7070 treatment significantly reduced tumor cell growth and increased radio- and chemotherapy efficacy against GBM cells under hypoxia. Our data suggests that E7070 has therapeutic potential as a radio-chemo-sensitizing in drug-resistant GBMs, representing an attractive strategy to improve the adjuvant therapy. We showed that CA9 and CA12 represent potentially valuable therapeutic targets that should be further investigated as useful diagnostic and prognostic biomarkers for GBM tailored therapy.
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19
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Avula SK, Rehman NU, Khan M, Halim SA, Khan A, Rafiq K, Csuk R, Das B, Al-Harrasi A. New synthetic 1H-1,2,3-triazole derivatives of 3-O-acetyl-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic acid from Boswellia sacra inhibit carbonic anhydrase II in vitro. Med Chem Res 2021. [DOI: 10.1007/s00044-021-02723-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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20
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Carbonic Anhydrase IX Promotes Human Cervical Cancer Cell Motility by Regulating PFKFB4 Expression. Cancers (Basel) 2021; 13:cancers13051174. [PMID: 33803236 PMCID: PMC7967120 DOI: 10.3390/cancers13051174] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy. Abstract Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. In this study, CAIX overexpression in SiHa cells increased cell migration and epithelial-to-mesenchymal transition (EMT). Silencing CAIX in the Caski cell line decreased the motility of cells and EMT. Furthermore, the RNA-sequencing analysis identified a target gene, bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB4), which is influenced by CAIX overexpression and knockdown. A positive correlation was found between CAIX expression and PFKFB4 levels in the cervical cancer of the TCGA database. Mechanistically, CAIX overexpression activated the phosphorylation of extracellular signal-regulated kinases (ERKs) to induce EMT and promote cell migration. In clinical results, human cervical cancer patients with CAIXhigh/PFKFB4high expression in the late stage had higher rates of lymph node metastasis and the shortest survival time. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy.
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Xing X, Yuan H, Liu H, Tan X, Zhao B, Wang Y, Ouyang J, Lin M, Liu X, Huang A. Quantitative Secretome Analysis Reveals Clinical Values of Carbonic Anhydrase II in Hepatocellular Carcinoma. GENOMICS PROTEOMICS & BIOINFORMATICS 2021; 19:94-107. [PMID: 33662630 PMCID: PMC8498920 DOI: 10.1016/j.gpb.2020.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/15/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022]
Abstract
Early detection and intervention are key strategies to reduce mortality, increase long-term survival, and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomic strategy was used to study the secretomes in conditioned media from HCC cancerous tissues, surrounding noncancerous tissues, and distal noncancerous tissues to identify diagnostic and prognostic biomarkers for HCC. In total, 22 and 49 dysregulated secretory proteins were identified in the cancerous and surrounding noncancerous tissues, respectively, compared with the distal noncancerous tissues. Among these proteins, carbonic anhydrase II (CA2) was identified to be significantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients compared with that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after radical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence and overall survival. Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition pathway. Taken together, this study identified a novel biomarker for HCC diagnosis and prognosis, and provided a valuable resource of HCC secretome for investigating serological biomarkers.
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Affiliation(s)
- Xiaohua Xing
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou 350004, China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Hui Yuan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Hongzhi Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Xionghong Tan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Jiahe Ouyang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Minjie Lin
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
| | - Xiaolong Liu
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou 350004, China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China.
| | - Aimin Huang
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou 350004, China.
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Aldera AP, Govender D. Carbonic anhydrase IX: a regulator of pH and participant in carcinogenesis. J Clin Pathol 2021; 74:jclinpath-2020-207073. [PMID: 33619217 DOI: 10.1136/jclinpath-2020-207073] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/31/2020] [Accepted: 01/24/2021] [Indexed: 11/04/2022]
Abstract
Carbonic anhydrase IX (CAIX) is a transmembrane metalloenzyme which is upregulated in tumour cells under hypoxic conditions. CAIX expression is induced by the accumulation of hypoxia-inducible factor-1α and has several downstream effects, including acidification of the extracellular pH, loss of cellular adhesion and increased tumour cell migration. CAIX is upregulated in a variety of solid organ tumours and has prognostic implications. High CAIX protein expression is a marker of poor prognosis in breast, lung, ovarian and bladder carcinomas. Conversely, low expression is an indicator of poor prognosis in clear cell renal cell carcinoma (CCRCC). CAIX immunohistochemistry is useful diagnostically to identify metastatic CCRCC, and the recently recognised clear cell papillary renal cell carcinoma. There is much interest in targeting CAIX with monoclonal antibodies and small molecule inhibitors. There are several small molecule inhibitors under development which have shown promising results in clinical trials. In this paper, we provide an overview of the role of CAIX in tumourigenesis and outline its use as a prognostic, diagnostic and therapeutic biomarker.
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Affiliation(s)
- Alessandro Pietro Aldera
- Division of Anatomical Pathology, University of Cape Town, Cape Town, South Africa
- JDW Pathology Inc, Cape Town, South Africa
| | - Dhirendra Govender
- Division of Anatomical Pathology, University of Cape Town, Cape Town, South Africa
- Anatomical Pathology, Pathcare Cape Town, Cape Town, South Africa
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23
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New amino acid clubbed Schiff bases inhibit carbonic anhydrase II, α-glucosidase, and urease enzymes: in silico and in vitro. Med Chem Res 2021. [DOI: 10.1007/s00044-020-02696-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Koltai T. Targeting the pH Paradigm at the Bedside: A Practical Approach. Int J Mol Sci 2020; 21:E9221. [PMID: 33287221 PMCID: PMC7730959 DOI: 10.3390/ijms21239221] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the "cancer problem"? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article's goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.
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Affiliation(s)
- Tomas Koltai
- Centro de Diagnostico y Tratamiento de la Obra Social del Personal de la Alimentacion, Talar de Pacheco, Buenos Aires 1617, Argentina
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25
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Ozensoy Guler O, Supuran CT, Capasso C. Carbonic anhydrase IX as a novel candidate in liquid biopsy. J Enzyme Inhib Med Chem 2020; 35:255-260. [PMID: 31790601 PMCID: PMC6896409 DOI: 10.1080/14756366.2019.1697251] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/13/2019] [Accepted: 11/16/2019] [Indexed: 12/15/2022] Open
Abstract
Among the diagnostic techniques for the identification of tumour biomarkers, the liquid biopsy is considered one that offers future research on precision diagnosis and treatment of tumours in a non-invasive manner. The approach consists of isolating tumor-derived components, such as circulating tumour cells (CTC), tumour cell-free DNA (ctDNA), and extracellular vesicles (EVs), from the patient peripheral blood fluids. These elements constitute a source of genomic and proteomic information for cancer treatment. Within the tumour-derived components of the body fluids, the enzyme indicated with the acronym CA IX and belonging to the superfamily of carbonic anhydrases (CA, EC 4.2.1.1) is a promising aspirant for checking tumours. CA IX is a transmembrane-CA isoform that is strongly overexpressed in many cancers being not much diffused in healthy tissues except the gastrointestinal tract. Here, it is summarised the role of CA IX as tumour-associated protein and its putative relationship in liquid biopsyfor diagnosing and monitoring cancer progression.
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Affiliation(s)
- Ozen Ozensoy Guler
- Department of Medical Biology, Faculty of Medicine, Yildirim Beyazit University, Ankara, Turkey
| | - Claudiu. T. Supuran
- Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze, Italy
| | - Clemente Capasso
- Department of Biology, Agriculture and Food Sciences, Institute of Biosciences and Bioresources, CNR, Napoli, Italy
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Khan A, Khan M, Halim SA, Khan ZA, Shafiq Z, Al-Harrasi A. Quinazolinones as Competitive Inhibitors of Carbonic Anhydrase-II (Human and Bovine): Synthesis, in-vitro, in-silico, Selectivity, and Kinetics Studies. Front Chem 2020; 8:598095. [PMID: 33335888 PMCID: PMC7736042 DOI: 10.3389/fchem.2020.598095] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 10/28/2020] [Indexed: 11/13/2022] Open
Abstract
Carbonic anhydrase-II (CA-II) is associated with glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. In search of potent CA-II inhibitors, a series of quinazolinones derivatives (4a-p) were synthesized and characterized by IR and NMR spectroscopy. The inhibitory potential of all the compounds was evaluated against bovine carbonic anhydrase-II (bCA-II) and human carbonic anhydrase-II (hCA-II), and compounds displayed moderate to significant inhibition with IC50 values of 8.9-67.3 and 14.0-59.6 μM, respectively. A preliminary structure-activity relationship suggested that the presence of a nitro group on the phenyl ring at R position contributes significantly to the overall activity. Kinetics studies of the most active inhibitor, 4d, against both bCA-II and hCA-II were performed to investigate the mode of inhibition and to determine the inhibition constants (Ki). According to the kinetics results, 4d is a competitive inhibitor of bCA-II and hCA-II with Ki values of 13.0 ± 0.013 and 14.25 ± 0.017 μM, respectively. However, the selectivity index reflects that the compounds 4g and 4o are more selective for hCA-II. The binding mode of these compounds within the active sites of bCA-II and hCA-II was investigated by structure-based molecular docking. The docking results are in complete agreement with the experimental findings.
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Affiliation(s)
- Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Majid Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
- International Center for Chemical and Biological Sciences, H. E. J. Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Zulfiqar Ali Khan
- Department of Chemistry, Government College University, Faisalabad, Pakistan
| | - Zahid Shafiq
- Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
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27
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Combined treatment with acetazolamide and cisplatin enhances the chemosensitivity of human head and neck squamous cell carcinoma TU868 cells. Arch Oral Biol 2020; 119:104905. [PMID: 32947166 DOI: 10.1016/j.archoralbio.2020.104905] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 05/21/2020] [Accepted: 08/31/2020] [Indexed: 12/17/2022]
Abstract
AIMS To investigate whether combination of acetazolamide and cisplatin can enhance the chemosensitivity of human head and neck squamous cell carcinoma (HNSCC) cell line TU868. METHODS MTT assay was performed to determine the effect of acetazolamide, cisplatin and their combination on the proliferation of TU868 cells. Then the effect of these 2 drugs on the expression of proliferation-related and apoptosis-related proteins was detected by Western blot. Moreover, the effect of acetazolamide and cisplatin on the expression of aquaporin-1 was detected by RT-qPCR. Loss-of-function assays was performed to assess whether the effect of acetazolamide and cisplatin on TU868 cells was mediated by aquaporin-1. The effect of acetazolamide and cisplatin on tumor cell growth was confirmed in mice by testing the tumor growth size. RESULTS Acetazolamide and cisplatin treatment displayed synergistic effects on the inhibition of TU868 cell growth compared with the drugs used alone. Moreover, the acetazolamide/cisplatin combination could decrease the level of PCNA but increase the level of p53; decrease the ratio of Bcl-2/Bax and increase the expression of caspase-3 compared with the single drug treated group. Moreover, we found that the combination also significantly inhibits aquaporin-1 expression. Loss-of-function assays suggested that the anti-tumor effect of these 2 drugs was achieved via affecting aquaporin-1. Consistent with the in vitro assays, combined treatment with acetazolamide and cisplatin significantly inhibits the tumor growth in mice compared with the single drug treated group. CONCLUSION These results demonstrated that combined treatment with acetazolamide and cisplatin could synergistically inhibit the malignant development of HNSCC cells.
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28
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Akocak S, Güzel-Akdemir Ö, Kishore Kumar Sanku R, Russom SS, Iorga BI, Supuran CT, Ilies MA. Pyridinium derivatives of 3-aminobenzenesulfonamide are nanomolar-potent inhibitors of tumor-expressed carbonic anhydrase isozymes CA IX and CA XII. Bioorg Chem 2020; 103:104204. [PMID: 32891000 DOI: 10.1016/j.bioorg.2020.104204] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/16/2020] [Accepted: 08/17/2020] [Indexed: 12/26/2022]
Abstract
Building on the conclusions of previous inhibition studies with pyridinium-benzenesulfonamides from our team and on the X-ray crystal structure of the lead compound identified, a series of 24 pyridinium derivatives of 3-aminobenzenesulfonamide was synthesized and investigated for carbonic anhydrase inhibition. The new pyridinium-sulfonamides were evaluated as inhibitors of four human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely CA I, CA II (cytosolic), CA IX and XII (transmembrane, tumor-associated forms). Excellent inhibitory activity in the nanomolar range was observed against CA IX with most of these sulfonamides, and against CA XII (nanomolar/sub-nanomolar) with some of the new compounds. These sulfonamides were generally potent inhibitors of CA II and CA I too. Docking studies revealed a preference of these compounds to bind the P1 hydrophobic site of CAs, supporting the observed inhibition profile. The salt-like nature of these positively charged sulfonamides can further focus the inhibitory ability on membrane-bound CA IX and CA XII and could efficiently decrease the viability of three human carcinomas under hypoxic conditions where these isozymes are over-expressed, thus recommending the new compounds as potential diagnostic tools or therapeutic agents.
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Affiliation(s)
- Suleyman Akocak
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia PA-19140, United States
| | - Özlen Güzel-Akdemir
- NEUROFARBA Department, Università degli Studi di Firenze, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy; Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazıt, Istanbul, Turkey
| | - Rajesh Kishore Kumar Sanku
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia PA-19140, United States
| | - Samson S Russom
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia PA-19140, United States
| | - Bogdan I Iorga
- Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles (ICSN), 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
| | - Claudiu T Supuran
- NEUROFARBA Department, Università degli Studi di Firenze, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
| | - Marc A Ilies
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia PA-19140, United States.
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Iorio J, Duranti C, Lottini T, Lastraioli E, Bagni G, Becchetti A, Arcangeli A. K V11.1 Potassium Channel and the Na +/H + Antiporter NHE1 Modulate Adhesion-Dependent Intracellular pH in Colorectal Cancer Cells. Front Pharmacol 2020; 11:848. [PMID: 32587517 PMCID: PMC7297984 DOI: 10.3389/fphar.2020.00848] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/22/2020] [Indexed: 12/16/2022] Open
Abstract
Increasing evidence indicates that ion channels and transporters cooperate in regulating different aspects of tumor pathophysiology. In cancer cells, H+/HCO3- transporters usually invert the transmembrane pH gradient typically observed in non-neoplastic cells, which is thought to contribute to cancer malignancy. To what extent the pH-regulating transporters are functionally linked to K+ channels, which are central regulators of cell membrane potential (Vm), is unclear. We thus investigated in colorectal cancer cells the implication of the pH-regulating transporters and KV11.1 (also known as hERG1) in the pH modifications stimulated by integrin-dependent cell adhesion. Colorectal cancer cell lines (HCT 116 and HT 29) were seeded onto β1 integrin-dependent substrates, collagen I and fibronectin. This led to a transient cytoplasmic alkalinization, which peaked at 90 min of incubation, lasted approximately 180 min, and was inhibited by antibodies blocking the β1 integrin. The effect was sensitive to amiloride (10 µM) and cariporide (5 µM), suggesting that it was mainly caused by the activity of the Na+/H+ antiporter NHE1. Blocking KV11.1 with E4031 shows that channel activity contributed to modulate the β1 integrin-dependent pHi increase. Interestingly, both NHE1 and KV11.1 modulated the colorectal cancer cell motility triggered by β1 integrin-dependent adhesion. Finally, the β1 integrin subunit, KV11.1 and NHE1 co-immunoprecipitated in colorectal cancer cells seeded onto Collagen I, suggesting the formation of a macromolecular complex following integrin-mediated adhesion. We conclude that the interaction between KV11.1, NHE1, and β1 integrin contributes to regulate colorectal cancer intracellular pH in relation to the tumor microenvironment, suggesting novel pharmacological targets to counteract pro-invasive and, hence, pro-metastatic behavior in colorectal cancer.
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Affiliation(s)
- Jessica Iorio
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Duranti
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Tiziano Lottini
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Elena Lastraioli
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giacomo Bagni
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy
| | - Annarosa Arcangeli
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Pratesi D, Matassini C, Goti A, Angeli A, Carta F, Supuran CT, Spanevello R, Cardona F. Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors. ACS Med Chem Lett 2020; 11:727-731. [PMID: 32435377 DOI: 10.1021/acsmedchemlett.9b00590] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/11/2020] [Indexed: 12/30/2022] Open
Abstract
The synthesis of selective inhibitors of human carbonic anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targeted pathology, and this was partially addressed with the introduction of a sugar moiety (the so-called "sugar approach"). Since glycomimetics are considered more selective than the parent sugars in inhibiting carbohydrate-processing enzyme, we explored the possibility of further tuning the selectivity of hCAs inhibitors by combining the sulfonamide moiety with a sugar analogue residue. In particular, we report the synthesis of two novel hCAs inhibitors 2 and 3 which feature the presence of a piperidine iminosugar and an additional carbohydrate moiety derived from levoglucosenone (1), a key intermediate derived from cellulose pyrolysis. Biological assays revealed that iminosugar 2 is a very strong inhibitor of the central nervous system (CNS) abundantly expressed hCA VII (K I of 7.4 nM) and showed a remarkable selectivity profile toward this isoform. Interestingly, the presence of levoglucosenone in glycomimetic 3 imparted a strong inhibitory activity toward the tumor associated hCA IX (K I of 35.9 nM).
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Affiliation(s)
- Debora Pratesi
- Dipartimento di Chimica “Ugo Schiff”, Università di Firenze, via della Lastruccia n. 3-13, Sesto Fiorentino, 50019 Firenze, Italy
| | - Camilla Matassini
- Dipartimento di Chimica “Ugo Schiff”, Università di Firenze, via della Lastruccia n. 3-13, Sesto Fiorentino, 50019 Firenze, Italy
| | - Andrea Goti
- Dipartimento di Chimica “Ugo Schiff”, Università di Firenze, via della Lastruccia n. 3-13, Sesto Fiorentino, 50019 Firenze, Italy
- Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), 70100 Bari, Italy
| | - Andrea Angeli
- Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
| | - Fabrizio Carta
- Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
| | - Claudiu T. Supuran
- Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
| | - Rolando Spanevello
- Instituto de Química Rosario, Facultad de Ciencias Bioquímica y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Suipacha 531, S2002LRK Rosario, Argentina
| | - Francesca Cardona
- Dipartimento di Chimica “Ugo Schiff”, Università di Firenze, via della Lastruccia n. 3-13, Sesto Fiorentino, 50019 Firenze, Italy
- Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), 70100 Bari, Italy
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Ur Rehman N, Halim SA, Khan M, Hussain H, Yar Khan H, Khan A, Abbas G, Rafiq K, Al-Harrasi A. Antiproliferative and Carbonic Anhydrase II Inhibitory Potential of Chemical Constituents from Lycium shawii and Aloe vera: Evidence from In Silico Target Fishing and In Vitro Testing. Pharmaceuticals (Basel) 2020; 13:E94. [PMID: 32414030 PMCID: PMC7281707 DOI: 10.3390/ph13050094] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/29/2020] [Accepted: 05/04/2020] [Indexed: 12/21/2022] Open
Abstract
Lycium shawii Roem. & Schult and resin of Aloe vera (L.) BURM. F. are commonly used in Omani traditional medication against various ailments. Herein, their antiproliferative and antioxidant potential was explored. Bioassay-guided fractionation of the methanol extract of both plants led to the isolation of 14 known compounds, viz., 1-9 from L. shawii and 10-20 from A. vera. Their structures were confirmed by combined spectroscopic techniques including 1D (1H and 13C) and 2D (HMBC, HSQC, COSY) nuclear magnetic resonance (NMR), and electrospray ionization-mass spectrometry (ESI-MS). The cytotoxic potential of isolates was tested against the triple-negative breast cancer cell line (MDA-MB-231). Compound 5 exhibited excellent antiproliferative activity in a range of 31 μM, followed by compounds 1-3, 7, and 12, which depicted IC50 values in the range of 35-60 μM, while 8, 6, and 9 also demonstrated IC50 values >72 μM. Subsequently, in silico target fishing was applied to predict the most potential cellular drug targets of the active compounds, using pharmacophore modeling and inverse molecular docking approach. The extensive in silico analysis suggests that our compounds may target carbonic anhydrase II (CA-II) to exert their anticancer activities. When tested on CA-II, compounds 5 (IC50 = 14.4 µM), 12 (IC50 = 23.3), and 2 (IC50 = 24.4 µM) showed excellent biological activities in vitro. Additionally, the ethyl acetate fraction of both plants showed promising antioxidant activity. Among the isolated compounds, 4 possesses the highest antioxidant (55 μM) activity followed by 14 (241 μM). The results indicated that compound 4 can be a promising candidate for antioxidant drugs, while compound 5 is a potential candidate for anticancer drugs.
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Affiliation(s)
- Najeeb Ur Rehman
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
| | - Sobia Ahsan Halim
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
| | - Majid Khan
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
- HEJ Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan
| | - Hidayat Hussain
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, 06120 Halle, Germany
| | - Husain Yar Khan
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
| | - Ajmal Khan
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
| | - Ghulam Abbas
- Department of Biological Sciences and Chemistry, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman;
| | - Kashif Rafiq
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
- Department of Chemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, P.O Box 33, 616 Birkat Al Mauz, Nizwa, Sultanate of Oman; (N.U.R.); (S.A.H.); (M.K.); (H.H.); (H.Y.K.); (A.K.); (K.R.)
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Yorulmaz N, Eroğlu E. DFT based QSARs for inhibitory activity of coumarins towards tumor-associated isoform (CA XII) of carbonic anhydrases. J Mol Struct 2020. [DOI: 10.1016/j.molstruc.2020.127844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Ward C, Meehan J, Gray ME, Murray AF, Argyle DJ, Kunkler IH, Langdon SP. The impact of tumour pH on cancer progression: strategies for clinical intervention. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:71-100. [PMID: 36046070 PMCID: PMC9400736 DOI: 10.37349/etat.2020.00005] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/05/2020] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H+-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets.
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Affiliation(s)
- Carol Ward
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - James Meehan
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Mark E Gray
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG Midlothian, UK
| | - Alan F Murray
- School of Engineering, Institute for Integrated Micro and Nano Systems, EH9 3JL Edinburgh, UK
| | - David J Argyle
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG Midlothian, UK
| | - Ian H Kunkler
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Simon P Langdon
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
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Liu Z, Bai Y, Xie F, Miao F, Du F. Comprehensive Analysis for Identifying Diagnostic and Prognostic Biomarkers in Colon Adenocarcinoma. DNA Cell Biol 2020; 39:599-614. [PMID: 32031891 DOI: 10.1089/dna.2019.5215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Colon adenocarcinoma (COAD) is a common noncutaneous carcinoma worldwide with high morbidity and mortality. Effective prevention methods are far from being met. Both diagnostic and prognostic models that can precisely and accurately predict the status and survival time of COAD are urgently needed. In the field of COAD, there have been limited studies on molecular biomarkers that can predict disease status and prognosis. Hence, an important task is to identify these biomarkers. We aimed to identify important risk genes that have the ability not only to diagnose tumors but also to predict overall survival. A comprehensive analysis was performed in this study. Finally, carbonic anhydrase 1 (CA1) and CA4 were identified as potential biomarkers due to their predictive roles in diagnosis and prognosis, and the results were further confirmed by a series of analyses. Overall, these findings are of great importance and may facilitate individualized treatment in diagnosis and prognosis.
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Affiliation(s)
- Zhisong Liu
- Faculty of Statistics, Tianjin University of Finance and Economics, Tianjin, China.,Department of Statistics, Tianjin University of Finance and Economics Pearl River College, Tianjin, China
| | - Yi Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.,Department of Hepatobiliary Surgery, First Central Hospital, Tianjin, China
| | - Fucun Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Fei Miao
- Department of Statistics, Tianjin University of Finance and Economics Pearl River College, Tianjin, China
| | - Fei Du
- Faculty of Statistics, Tianjin University of Finance and Economics, Tianjin, China
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Koyuncu I, Gonel A, Durgun M, Kocyigit A, Yuksekdag O, Supuran CT. Assessment of the antiproliferative and apoptotic roles of sulfonamide carbonic anhydrase IX inhibitors in HeLa cancer cell line. J Enzyme Inhib Med Chem 2019; 34:75-86. [PMID: 30362386 PMCID: PMC6211230 DOI: 10.1080/14756366.2018.1524380] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 09/12/2018] [Accepted: 09/12/2018] [Indexed: 12/22/2022] Open
Abstract
Carbonic anhydrase IX (CA IX) has recently been validated as an antitumor/antimetastatic drug target. In this study, we examined the underlying molecular mechanisms and the anticancer activity of sulfonamide CA IX inhibitors against cervical cancer cell lines. The effects of several sulfonamides on HeLa, MDA-MB-231, HT-29 cancer cell lines, and normal cell lines (HEK-293, PNT-1A) viability were determined. The compounds showed high cytotoxic and apoptotic activities, mainly against HeLa cells overexpressing CA IX. We were also examined for intracellular reactive oxygen species (ROS) production; intra-/extracellular pH changes, for inhibition of cell proliferation, cellular mitochondrial membrane potential change and for the detection of caspase 3, 8, 9, and CA IX protein levels. Of the investigated sulfonamides, one compound was found to possess high cytotoxic and anti-proliferative effects in HeLa cells. The cytotoxic effect occurred via apoptosis, being accompanied by a return of pHe/pHi towards normal values as for other CA IX inhibitors investigated earlier.
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Affiliation(s)
- Ismail Koyuncu
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Ataman Gonel
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Mustafa Durgun
- Department of Chemistry, Faculty of Arts and Sciences, Harran University, Sanliurfa, Turkey
| | - Abdurrahim Kocyigit
- Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ozgur Yuksekdag
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Claudiu T. Supuran
- Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Sesto Fiorentino (Florence), Italy
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Xu J, Zhang J, Shan F, Wen J, Wang Y. SSTR5‑AS1 functions as a ceRNA to regulate CA2 by sponging miR‑15b‑5p for the development and prognosis of HBV‑related hepatocellular carcinoma. Mol Med Rep 2019; 20:5021-5031. [PMID: 31638225 PMCID: PMC6854603 DOI: 10.3892/mmr.2019.10736] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/29/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have been implicated in the development and progression of cancer. However, the mechanisms of lncRNAs in hepatitis B virus (HBV) infection-induced hepatocellular carcinoma (HCC) remain unclear. The study aimed to reveal the roles of lncRNAs for HBV-HCC based on the hypothesis of competing endogenous RNA (ceRNA). The lncRNA (GSE27462), miRNA (GSE76903) and mRNA (GSE121248) expression profiles were collected from the Gene Expression Omnibus database. Differentially expressed lncRNAs (DELs), genes (DEGs) and miRNAs (DEMs) were identified using the LIMMA or EdgeR package, respectively. The ceRNA network was constructed based on interaction pairs between miRNAs and mRNAs/lncRNAs. The functions of DEGs in the ceRNA network were predicted using the DAVID database, which was overlapped with the known HCC pathways of Comparative Toxicogenomics Database (CTD) to construct the HCC-related ceRNA network. The prognosis values [overall survival, (OS); recurrence-free survival (RFS)] of genes were validated using the Cancer Genome Atlas (TCGA) data with Cox regression analysis. The present study screened 38 DELs, 127 DEMs and 721 DEGs. A ceRNA network was constructed among 17 DELs, 12 DEMs and 173 DEGs, including the FAM138B-hsa-miR-30c-CCNE2/RRM2 and SSTR5-AS1-hsa-miR-15b-5p-CA2 ceRNA axes. Function enrichment analysis revealed the genes in the ceRNA network that participated in the p53 signaling pathway [cyclin E2 (CCNE2), ribonucleotide reductase M2 subunit (RRM2)] and nitrogen metabolism [carbonic anhydrase 2 (CA2)], which were also included in the pathways of the CTD. Univariate Cox regression analysis revealed that six RNAs (2 DELs: FAM138B, SSTR5-AS1; 2 DEMs: hsa-miR-149, hsa-miR-7; 2 DEGs: CCNE2, RRM2) were significantly associated with OS; while seven RNAs (1 DEL: LINC00284; 3 DEMs: hsa-miR-7, hsa-miR-15b, hsa-miR-30c-2; and 3 DEGs: RRM2, CCNE2, CA2) were significantly associated with RFS. In conclusion, FAM138B-hsa-miR-30c-CCNE2/RRM2 and the SSTR5-AS1-hsa-miR-15b-5p-CA2 ceRNA axes may be important mechanisms for HBV-related HCC.
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Affiliation(s)
- Jing Xu
- Infectious Diseases Division, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Jing Zhang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Fenglian Shan
- Infectious Diseases Division, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Jie Wen
- Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Yue Wang
- Infectious Diseases Division, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
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Abstract
INTRODUCTION The physiologic importance of fast CO2/HCO3- interconversion in various tissues requires the presence of carbonic anhydrase (CA, EC 4.2.1.1). Fourteen CA isozymes are present in humans, all of them being used as biomarkers. AREAS COVERED A great number of patents and articles were focused on the use of CA isozymes as biomarkers for various diseases and syndromes in the recent years, in an ascending trend over the last decade. The review highlights the most important studies related with each isozyme and covers the most recent patent literature. EXPERT OPINION The CAs biomarker research area expanded significantly in recent years, shifting from the predominant use of CA IX and CA XII in cancer diagnostic, staging, and prognosis towards a wider use of CA isozymes as disease biomarkers. CA isozymes are currently used either alone, in tandem with other CA isozymes and/or in combination with other proteins for the detection, staging, and prognosis of a huge repertoire of human dysfunctions and diseases, ranging from mild transformation of the normal tissues to extreme shifts in tissue organization and function. The techniques used for their detection/quantitation and the state-of-the-art in each clinical application are presented through relevant clinical examples and corresponding statistical data.
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Affiliation(s)
- Sabina Zamanova
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA
| | - Ahmed M Shabana
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA
| | - Utpal K Mondal
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA
| | - Marc A Ilies
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA.,b Temple Fox Chase Cancer Center , Philadelphia , PA , USA
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Saghafi T, Taheri RA, Parkkila S, Emameh RZ. Phytochemicals as Modulators of Long Non-Coding RNAs and Inhibitors of Cancer-Related Carbonic Anhydrases. Int J Mol Sci 2019; 20:E2939. [PMID: 31208095 PMCID: PMC6627131 DOI: 10.3390/ijms20122939] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 01/17/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are classified as a group of transcripts which regulate various biological processes, such as RNA processing, epigenetic control, and signaling pathways. According to recent studies, lncRNAs are dysregulated in cancer and play an important role in cancer incidence and spreading. There is also an association between lncRNAs and the overexpression of some tumor-associated proteins, including carbonic anhydrases II, IX, and XII (CA II, CA IX, and CA XII). Therefore, not only CA inhibition, but also lncRNA modulation, could represent an attractive strategy for cancer prevention and therapy. Experimental studies have suggested that herbal compounds regulate the expression of many lncRNAs involved in cancer, such as HOTAIR (HOX transcript antisense RNA), H19, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), PCGEM1 (Prostate cancer gene expression marker 1), PVT1, etc. These plant-derived drugs or phytochemicals include resveratrol, curcumin, genistein, quercetin, epigallocatechin-3-galate, camptothcin, and 3,3'-diindolylmethane. More comprehensive information about lncRNA modulation via phytochemicals would be helpful for the administration of new herbal derivatives in cancer therapy. In this review, we describe the state-of-the-art and potential of phytochemicals as modulators of lncRNAs in different types of cancers.
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Affiliation(s)
- Tayebeh Saghafi
- Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), 14965/161, Tehran, Iran.
| | - Ramezan Ali Taheri
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O.Box 14965/161 Tehran, Iran.
| | - Seppo Parkkila
- Faculty of Medicine and Health Technology, Tampere University, FI-33520 Tampere, Finland.
- Fimlab Laboratories Ltd. and Tampere University Hospital, FI-33520 Tampere, Finland.
| | - Reza Zolfaghari Emameh
- Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), 14965/161, Tehran, Iran.
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Wang Z, An HW, Hou D, Wang M, Zeng X, Zheng R, Wang L, Wang K, Wang H, Xu W. Addressable Peptide Self-Assembly on the Cancer Cell Membrane for Sensitizing Chemotherapy of Renal Cell Carcinoma. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1807175. [PMID: 30663139 DOI: 10.1002/adma.201807175] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/02/2019] [Indexed: 05/06/2023]
Abstract
Chemotherapy has been validated unavailable for treatment of renal cell carcinoma (RCC) in clinic due to its intrinsic drug resistance. Sensitization of chemo-drug response plays a crucial role in RCC treatment and increase of patient survival. Herein, a recognition-reaction-aggregation (RRA) cascaded strategy is utilized to in situ construct peptide-based superstructures on the renal cancer cell membrane, enabling specifically perturbing the permeability of cell membranes and enhancing chemo-drug sensitivity in vitro and in vivo. First, P1-DBCO can specifically recognize renal cancer cells by targeting carbonic anhydrase IX. Subsequently, P2-N3 is introduced and efficiently reacts with P1-DBCO to form a peptide P3, which exhibits enhanced hydrophobicity and simultaneously aggregates into a superstructure. Interestingly, the superstructure retains on the cell membrane and perturbs its integrity/permeability, allowing more doxorubicin (DOX) uptaken by renal cancer cells. Owing to this increased influx, the IC50 is significantly reduced by nearly 3.5-fold compared with that treated with free DOX. Finally, RRA strategy significantly inhibits the tumor growth of xenografted mice with a 3.2-fold enhanced inhibition rate compared with that treated with free DOX. In summary, this newly developed RRA strategy will open a new avenue for chemically engineering cell membranes with diverse biomedical applications.
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Affiliation(s)
- Ziqi Wang
- Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
| | - Hong-Wei An
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Yuquan Road, Beijing, 100049, China
| | - Dayong Hou
- Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
| | - Mandi Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
| | - Xiangzhong Zeng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
| | - Rui Zheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
| | - Lu Wang
- Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China
| | - Keliang Wang
- Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China
| | - Hao Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wanhai Xu
- Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin, 150001, China
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Cho EJ, Yu SJ, Kim K, Cho H, Cho YY, Lee YB, Lee JH, Kim YJ, Youn H, Yoon JH. Carbonic anhydrase-IX inhibition enhances the efficacy of hexokinase II inhibitor for hepatocellular carcinoma in a murine model. J Bioenerg Biomembr 2019; 51:121-129. [DOI: 10.1007/s10863-019-09788-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 02/05/2019] [Indexed: 12/14/2022]
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Song Y, Wang LY, Liu F, Li YT, Wu ZY, Yan CW. Simultaneously enhancing the in vitro/in vivo performances of acetazolamide using proline as a zwitterionic coformer for cocrystallization. CrystEngComm 2019. [DOI: 10.1039/c9ce00270g] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The synthesized first acetazolamide zwitterionic cocrystal highlights simultaneously-increasing solubility and permeability of acetazolamide, which successfully translate into enhanced bioavailability.
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Affiliation(s)
- Yu Song
- School of Medicine and Pharmacy and College of Marine Life Science
- Ocean University of China
- Qingdao
- PR China
| | - Ling-Yang Wang
- School of Medicine and Pharmacy and College of Marine Life Science
- Ocean University of China
- Qingdao
- PR China
| | - Fang Liu
- School of Medicine and Pharmacy and College of Marine Life Science
- Ocean University of China
- Qingdao
- PR China
| | - Yan-Tuan Li
- School of Medicine and Pharmacy and College of Marine Life Science
- Ocean University of China
- Qingdao
- PR China
- Laboratory for Marine Drugs and Bioproducts
| | - Zhi-Yong Wu
- School of Medicine and Pharmacy and College of Marine Life Science
- Ocean University of China
- Qingdao
- PR China
| | - Cui-Wei Yan
- School of Medicine and Pharmacy and College of Marine Life Science
- Ocean University of China
- Qingdao
- PR China
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Koyuncu I, Gonel A, Kocyigit A, Temiz E, Durgun M, Supuran CT. Selective inhibition of carbonic anhydrase-IX by sulphonamide derivatives induces pH and reactive oxygen species-mediated apoptosis in cervical cancer HeLa cells. J Enzyme Inhib Med Chem 2018; 33:1137-1149. [PMID: 30001631 PMCID: PMC6052416 DOI: 10.1080/14756366.2018.1481403] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/23/2018] [Accepted: 05/23/2018] [Indexed: 01/07/2023] Open
Abstract
Selective inhibition with sulphonamides of carbonic anhydrase (CA) IX reduces cell proliferation and induces apoptosis in human cancer cells. The effect on CA IX expression of seven previously synthesised sulphonamide inhibitors, with high affinity for CA IX, as well as their effect on the proliferation/apoptosis of cancer/normal cell lines was investigated. Two normal and three human cancer cell lines were used. Treatment resulted in dose- and time-dependent inhibition of the growth of various cancer cell lines. One compound showed remarkably high toxicity towards CA IX-positive HeLa cells. The mechanisms of apoptosis induction were determined with Annexin-V and AO/EB staining, cleaved caspases (caspase-3, caspase-8, caspase-9) and cleaved PARP activation, reactive oxygen species production (ROS), mitochondrial membrane potential (MMP), intracellular pH (pHi), extracellular pH (pHe), lactate level and cell cycle analysis. The autophagy induction mechanisms were also investigated. The modulation of apoptotic and autophagic genes (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin and LC3) was measured using real time PCR. The positive staining using γ-H2AX and AO/EB dye, showed increased cleaved caspase-3, caspase-8, caspase-9, increased ROS production, MMP and enhanced mRNA expression of apoptotic genes, suggesting that anticancer effects are also exerted through its apoptosis-inducing properties. Our results show that such sulphonamides might have the potential as new leads for detailed investigations against CA IX-positive cervical cancers.
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Affiliation(s)
- Ismail Koyuncu
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Ataman Gonel
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Abdurrahim Kocyigit
- Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ebru Temiz
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Mustafa Durgun
- Department of Chemistry, Faculty of Arts and Sciences, Harran University, Sanliurfa, Turkey
| | - Claudiu T. Supuran
- Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Polo Scientifico, Sesto Fiorentino, Florence, Italy
- Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy
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Karakuş F, Eyol E, Yılmaz K, Ünüvar S. Inhibition of cell proliferation, migration and colony formation of LS174T Cells by carbonic anhydrase inhibitor. Afr Health Sci 2018; 18:1303-1310. [PMID: 30766596 PMCID: PMC6354875 DOI: 10.4314/ahs.v18i4.51] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Metastasis is the leading cause of cancer deaths. Migration of tumor cells is an important stage in metastasis. Therefore, recent studies have focused on clarifying migration and migration-dependent cell functions such as angiogenesis, wound healing, and invasion. Objectives In the present study, we aimed to investigate the effect of acetazolamide, which is a classical carbonic anhydrase inhibitor, on the cell viability, migration, and colony forming capacity of human LS174T colorectal cancer cells. Methods Three different cell culture techniques (MTT test, wound healing and clonogenic assay) were performed in this in vitro study on colorectal cancer cells. Results Acetazolamide reduced the cell viability, migration and colony formation ability of cells depending on dose. There was no significant difference between the cells treated with acetazolamide with 1 µM dose and the control. However, it can be concluded that acetazolamide exerts its effect on human colorectal cancer cells at 10-1000 µM concentrations. Conclusion Acetazolamide was observed to significantly inhibit the cell viability, colony forming capacity, and migration ability in the culture medium of LS174T cells. This inhibitor effect of acetazolamide was observed to be dependent on the concentration in medium.
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Alsaab HO, Sau S, Alzhrani RM, Cheriyan VT, Polin LA, Vaishampayan U, Rishi AK, Iyer AK. Tumor hypoxia directed multimodal nanotherapy for overcoming drug resistance in renal cell carcinoma and reprogramming macrophages. Biomaterials 2018; 183:280-294. [PMID: 30179778 PMCID: PMC6414719 DOI: 10.1016/j.biomaterials.2018.08.053] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/24/2018] [Accepted: 08/26/2018] [Indexed: 12/24/2022]
Abstract
Drug resistance is one of the significant clinical burden in renal cell carcinoma (RCC). The development of drug resistance is attributed to many factors, including impairment of apoptosis, elevation of carbonic anhydrase IX (CA IX, a marker of tumor hypoxia), and infiltration of tumorigenic immune cells. To alleviate the drug resistance, we have used Sorafenib (Sor) in combination with tumor hypoxia directed nanoparticle (NP) loaded with a new class of apoptosis inducer, CFM 4.16 (C4.16), namely CA IX-C4.16. The NP is designed to selectively deliver the payload to the hypoxic tumor (core), provoke superior cell death in parental (WT) and Everolimus-resistant (Evr-res) RCC and selectively downmodulate tumorigenic M2-macrophage. Copper-free 'click' chemistry was utilized for conjugating SMA-TPGS with Acetazolamide (ATZ, a CA IX-specific targeting ligand). The NP was further tagged with a clinically approved NIR dye (S0456) for evaluating hypoxic tumor core penetration and organ distribution. Imaging of tumor spheroid treated with NIR dye-labeled CA IX-SMA-TPGS revealed remarkable tumor core penetration that was modulated by CA IX-mediated targeting in hypoxic-A498 RCC cells. The significant cell killing effect with synergistic combination index (CI) of CA IX-C4.16 and Sor treatment suggests efficient reversal of Evr-resistance in A498 cells. The CA IX directed nanoplatform in combination with Sor has shown multiple benefits in overcoming drug resistance through (i) inhibition of p-AKT, (ii) upregulation of tumoricidal M1 macrophages resulting in induction of caspase 3/7 mediated apoptosis of Evr-res A498 cells in macrophage-RCC co-culturing condition, (iii) significant in vitro and in vivo Evr-res A498 tumor growth inhibition as compared to individual therapy, and (iv) untraceable liver and kidney toxicity in mice. Near-infrared (NIR) imaging of CA IX-SMA-TPGS-S0456 in Evr-res A498 RCC model exhibited significant accumulation of CA IX-oligomer in tumor core with >3-fold higher tumor uptake as compared to control. In conclusion, this proof-of-concept study demonstrates versatile tumor hypoxia directed nanoplatform that can work in synergy with existing drugs for reversing drug-resistance in RCC accompanied with re-education of tumor-associated macrophages, that could be applied universally for several hypoxic tumors.
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Affiliation(s)
- Hashem O Alsaab
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif, 25671, Saudi Arabia
| | - Samaresh Sau
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA.
| | - Rami M Alzhrani
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA; Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif, 25671, Saudi Arabia
| | | | - Lisa A Polin
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Ulka Vaishampayan
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Arun K Rishi
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA; Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.
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Aggarwal K, Banik M, Medellin B, Que EL. In Situ Photoregulation of Carbonic Anhydrase Activity Using Azobenzenesulfonamides. Biochemistry 2018; 58:48-53. [PMID: 30358990 DOI: 10.1021/acs.biochem.8b00947] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We report two small molecule azobenzenesulfonamide probes, CAP1 and CAP2, capable of photomodulating the activity of carbonic anhydrase (CA) on demand. In the trans form, CAP azobenzene probes adopt a linear shape, making them suitable for occupying the CA active site and interacting with Zn2+, thereby inhibiting enzyme activity. Following irradiation with either 365 or 410 nm light, the CAP probes isomerize to their cis form. Because of the change in steric profile, the probe exits the active site, and the activity of the enzyme is restored. The cis isomer can revert back to the trans isomer through thermal relaxation or via photoirradiation with 460 nm light and thereby inhibit protein activity again. This process can be repeated multiple times without any photodegradation and thus can be used to inhibit or activate the protein reversibly. Importantly, we demonstrate our ability to apply CAP azobenzene probes to regulate CA activity both in an isolated protein solution and in live cells, where the two isomers of CAP1 differentially regulate the intracellular cytosolic pH.
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Affiliation(s)
- Kanchan Aggarwal
- Department of Chemistry , The University of Texas at Austin , 105 East 24th Street, Stop A5300 , Austin , Texas 78712 , United States
| | - Mandira Banik
- Department of Chemistry , The University of Texas at Austin , 105 East 24th Street, Stop A5300 , Austin , Texas 78712 , United States
| | - Brenda Medellin
- Department of Molecular Biosciences and Institute for Cellular and Molecular Biology , The University of Texas at Austin , 100 East 24th Street, Stop A5000 , Austin , Texas 78712 , United States
| | - Emily L Que
- Department of Chemistry , The University of Texas at Austin , 105 East 24th Street, Stop A5300 , Austin , Texas 78712 , United States
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Okuno K, Matsubara T, Nakamura T, Iino T, Kakimoto T, Asanuma K, Matsumine A, Sudo A. Carbonic anhydrase IX enhances tumor cell proliferation and tumor progression in osteosarcoma. Onco Targets Ther 2018; 11:6879-6886. [PMID: 30349321 PMCID: PMC6190629 DOI: 10.2147/ott.s177605] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Purpose We investigated the effect of carbonic anhydrase IX (CA IX) inhibitor under hypoxia and normoxia in SaOS2 human osteosarcoma cell line. We also evaluated the expression of CA IX in 27 patients diagnosed with osteosarcoma. Materials and methods CA IX expression in SaOS2 cells cultured under different oxygen tensions was analyzed by Western blotting. To evaluate the effect of CA IX inhibitor, MTS cell viability assay was performed after cells were treated with various concentrations of doxorubicin with or without a CA IX inhibitor. Finally, CA IX expression in patient-derived osteosarcoma samples was evaluated by immunohistochemistry. Results Treatment with CA IX inhibitor significantly suppressed cell proliferation and migration under hypoxic conditions. CA IX expression was observed in 81% of 27 patients. The 5-year survival rates in patients with high and low stain scores were 43.8% and 81.8%, respectively. Conclusion CA IX inhibitors have the potential to suppress cell proliferation, migration, and chemoresistance.
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Affiliation(s)
- Kazuma Okuno
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan, .,Department of Orthopedic Surgery, Ise Red Cross Hospital, Ise, Japan,
| | - Takao Matsubara
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan,
| | - Tomoki Nakamura
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan,
| | - Takahiro Iino
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan,
| | - Takuya Kakimoto
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan,
| | - Kunihiro Asanuma
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan,
| | - Akihiko Matsumine
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan, .,Department of Orthopedic Surgery, Fukui University Graduate School of Medicine, Fukui, Japan
| | - Akihiro Sudo
- Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan,
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Lacroix R, Rozeman EA, Kreutz M, Renner K, Blank CU. Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol Immunother 2018; 67:1331-1348. [PMID: 29974196 PMCID: PMC11028141 DOI: 10.1007/s00262-018-2195-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 06/29/2018] [Indexed: 12/21/2022]
Abstract
Checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) monoclonal antibodies have changed profoundly the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and bladder cancer. Currently, they are tested in various tumor entities as monotherapy or in combination with chemotherapies or targeted therapies. However, only a subgroup of patients benefit from checkpoint blockade (combinations). This raises the question, which all mechanisms inhibit T cell function in the tumor environment, restricting the efficacy of these immunotherapeutic approaches. Serum activity of lactate dehydrogenase, likely reflecting the glycolytic activity of the tumor cells and thus acidity within the tumor microenvironment, turned out to be one of the strongest markers predicting response to checkpoint inhibition. In this review, we discuss the impact of tumor-associated acidity on the efficacy of T cell-mediated cancer immunotherapy and possible approaches to break this barrier.
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Affiliation(s)
- Ruben Lacroix
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Elisa A Rozeman
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marina Kreutz
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Kathrin Renner
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Christian U Blank
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
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In vitro effect of carbonic anhydrase inhibitor acetazolamide on cell viability, migration and colony formation of colorectal cancer cells. Biologia (Bratisl) 2018. [DOI: 10.2478/s11756-018-0064-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Angapelly S, Angeli A, Khan AJ, Sri Ramya PV, Supuran CT, Arifuddin M. Synthesis and Biological Evaluation of 4-Sulfamoylphenyl/Sulfocoumarin Carboxamides as Selective Inhibitors of Carbonic Anhydrase Isoforms hCA II, IX, and XII. ChemMedChem 2018; 13:1165-1171. [PMID: 29675887 DOI: 10.1002/cmdc.201800180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/16/2018] [Indexed: 11/08/2022]
Abstract
With the aim to develop potent and selective human carbonic anhydrase inhibitors (hCAIs), we synthesized 4-sulfamoylphenyl/sulfocoumarin benzamides (series 5 a-r and series 7 a-q) and evaluated their inhibition profiles against five isoforms of the zinc-containing human carbonic anhydrase (hCA, EC 4.2.1.1): cytosolic hCA I and II, and the transmembrane isozymes hCA IV, IX, and XII. Compounds 5 a-r were found to selectively inhibit hCA II in the nanomolar range, while being less effective against the other hCA isoforms. As noted from the literature, sulfocoumarin (1,2-benzoxathiine 2,2-dioxide) acts as a "prodrug" inhibitor and is hydrolyzed by the esterase activity of hCA to form 2-hydroxyphenylvinylsulfonic acid, which thereafter binds to the enzyme in a manner similar to that of coumarins and sulfoxocoumarins. All these sulfocoumarins (compounds 7 a-q) were found to be very weak or ineffective as inhibitors of the housekeeping off-target hCA isoforms I and II, and effectively inhibited the transmembrane tumor-associated isoforms IX and XII in the high nanomolar to micromolar ranges. Further structural modifications of these molecules could be useful for the development of effective hCA inhibitors used for the treatment of glaucoma, epilepsy, and cancer.
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Affiliation(s)
- Srinivas Angapelly
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India
| | - Andrea Angeli
- NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
| | - Arbaj Jabbar Khan
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India
| | - P V Sri Ramya
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India
| | - Claudiu T Supuran
- NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
| | - Mohammed Arifuddin
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India
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Dalloul HMM, El-Nwairy KA, Shorafa AZ, Abu Samaha AS. Synthesis and antimicrobial activities evaluation of some new thiadiazinone and thiadiazepinone derivatives bearing sulfonamide moiety. PHOSPHORUS SULFUR 2018. [DOI: 10.1080/10426507.2017.1417292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Hany M. M. Dalloul
- Department of Chemistry, Faculty of Applied Science, Alaqsa University of Gaza, Gaza, Gaza Strip, Palestine
| | - Khaled A. El-Nwairy
- Ministry of Education & Higher Education, Beirut street, Southern remal, Gaza, Gaza Strip, Palestine
| | - Ali Z. Shorafa
- Ministry of Education & Higher Education, Beirut street, Southern remal, Gaza, Gaza Strip, Palestine
| | - Ahmed S. Abu Samaha
- Department of Biology, Faculty of Applied Science, Alaqsa University of Gaza, Gaza, Gaza Strip, Palestine
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