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Carbonic Anhydrase Inhibitors in Oncology.

Claudiu T Supuran1, Andrea Angeli2

  • 1Department of NEUROFARBA Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Florence, Italy.

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Summary

Carbonic anhydrase IX (CA IX) and XII (CA XII) are key targets in hypoxic tumors, regulating pH and survival. New strategies combine CA inhibition with other pathways for precision cancer therapy.

Keywords:
AntibodyCarbonic anhydraseFerroptosisMetalloenzymeOncologySLC-0111

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Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Tumor hypoxia and acidosis are critical hallmarks of the tumor microenvironment, driving cancer progression and therapeutic resistance.
  • Carbonic anhydrase IX (CA IX) and carbonic anhydrase XII (CA XII) are key molecular mediators, crucial for maintaining pH homeostasis and tumor cell survival under hypoxic stress.

Purpose of the Study:

  • To explore the therapeutic potential of targeting CA IX and CA XII in cancer.
  • To investigate the intersection of CA IX/XII with metabolic and redox pathways for novel therapeutic strategies.
  • To review advancements in small-molecule inhibitors and antibody-based approaches for CA isoform targeting.

Main Methods:

  • Review of recent findings on CA IX and CA XII roles in pH regulation, metabolism, and redox pathways.
  • Analysis of small-molecule inhibitors targeting CA isoforms, including those in clinical trials.
  • Evaluation of antibody-based therapeutic and diagnostic approaches, including conjugates.

Main Results:

  • CA IX and CA XII are not only vital for pH regulation but also influence ferroptosis, glutathione metabolism, and mitochondrial iron-sulfur cluster biogenesis.
  • Dual-target inhibitors combining CA IX/XII inhibition with other pathway modulations are emerging.
  • Antibody-based strategies are advancing for imaging, radioimmunotherapy, and drug delivery.

Conclusions:

  • Targeting CA IX and CA XII offers a promising strategy for exploiting metabolic vulnerabilities in hypoxic tumors.
  • Rational polypharmacology, co-targeting CA IX/XII with complementary pathways, represents a future direction in precision oncology.
  • Developing novel inhibitors and antibody-based therapies holds significant potential for improved cancer treatment outcomes.