Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

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Abstract

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with a release of the proton. CA, especially CAIX and CAXII isoforms gained the attention of many researchers interested in anticancer drug design due to pivotal functions of enzymes in the cancer cell metastasis and response to hypoxia, and their expression restricted to malignant cells. This offers an opportunity to develop new targeted therapies with fewer side effects. Continuous efforts led to the discovery of a series of diverse compounds with the most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule and antibody-based targeting of CAIX/CAXII in cancer.

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Cancer growth and progression are associated with immune suppression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. Monoclonal antibodies that target immune checkpoints provided an immense breakthrough in cancer therapeutics. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under clinical trials. Recent reports have shown that patients with various malignancies benefit from immune checkpoint inhibitor treatment. However, mainstream initiation of immune checkpoint therapy to treat cancers is obstructed by the low response rate and immune-related adverse events in some cancer patients. This has given rise to the need for developing sets of biomarkers that predict the response to immune checkpoint blockade and immune-related adverse events. In this review, we discuss different predictive biomarkers for anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors, including immune cells, PD-L1 overexpression, neoantigens, and genetic and epigenetic signatures. Potential approaches for further developing highly reliable predictive biomarkers should facilitate patient selection for and decision-making related to immune checkpoint inhibitor-based therapies.

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Jawad Fares, Mohamad Y. Fares, Hussein H. Khachfe … (2020)

Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

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The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy

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Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFĸB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.

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Author and article information

Journal

Journal ID (nlm-ta): J Enzyme Inhib Med Chem

Journal ID (iso-abbrev): J Enzyme Inhib Med Chem

Title: Journal of Enzyme Inhibition and Medicinal Chemistry

Publisher: Taylor & Francis

ISSN (Print): 1475-6366

ISSN (Electronic): 1475-6374

Publication date (Electronic, pub): 4 May 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 4 May 2022

Volume: 37

Issue: 1

Pages: 1278-1298

Affiliations

[a ]Department of Molecular Biotechnology and Genetics, Laboratory of Cytogenetics, University of Lodz , Lodz, Poland

[b ]Doctoral School of Exact and Natural Sciences, University of Lodz , Lodz, Poland

[c ]Institute of Pharmaceutical Research, GLA University , Mathura, India

[d ]Department of Chemistry, Siedlce University of Natural Sciences and Humanities , Siedlce, Poland

[e ]Department of Gastrointestinal Endoscopy, Wl. Bieganski Hospital , Lodz, Poland

Author notes

[*]

M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, Haryana, India.

CONTACT Mateusz Kciuk mateusz.kciuk@ 123456edu.uni.lodz.pl Department of Molecular Biotechnology and Genetics, Laboratory of Cytogenetics, University of Lodz , Banacha 12/16, 90-237 Lodz, Poland

Article

Publisher ID: 2052868

DOI: 10.1080/14756366.2022.2052868

PMC ID: 9090362

PubMed ID: 35506234

SO-VID: da177fe9-21f0-417e-a4e7-fba4a148f73b

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

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Cancer Immunotherapy

Most cited references 212

Immune checkpoint inhibitors: recent progress and potential biomarkers

Molecular principles of metastasis: a hallmark of cancer revisited

The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy

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