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Pharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions |
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| Authors: | Fangli Chen Emilia Licarete Xue Wu Daniela Petrusca Callista Maguire Max Jacobsen Austyn Colter George E Sandusky Magdalena Czader Maegan L Capitano James P Ropa H Scott Boswell Fabrizio Carta Claudiu T Supuran Brian Parkin Melissa L Fishel Heiko Konig |
| Institution: | 1. Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana, USA
Contribution: Conceptualization (lead), Formal analysis (lead), Methodology (lead), Writing - review & editing (lead);2. Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana, USA Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania Contribution: Formal analysis (supporting), Methodology (supporting), Writing - review & editing (supporting);3. Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana, USA;4. Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana, USA Contribution: Formal analysis (supporting), Writing - review & editing (supporting);5. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA Contribution: Methodology (supporting);6. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA Contribution: Formal analysis (supporting), Methodology (supporting);7. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA Contribution: Formal analysis (supporting), Methodology (supporting), Writing - review & editing (supporting);8. Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, Indiana, USA Contribution: Formal analysis (supporting), Methodology (supporting);9. NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Firenze, Italy Contribution: Resources (supporting);10. Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA Contribution: Formal analysis (supporting), Methodology (supporting) |
| Abstract: | Acute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O2)-deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and CD33 have been established in recent years, survival rates remain unsatisfactory, which indicates that other, yet unrecognized, mechanisms influence the ability of AML cells to escape cell death and to proliferate in hypoxic environments. Our data illustrates that Carbonic Anhydrases IX and XII (CA IX/XII) are critical for leukaemic cell survival in the O2-deprived milieu. CA IX and XII function as transmembrane proteins that mediate intracellular pH under low O2 conditions. Because maintaining a neutral pH represents a key survival mechanism for tumour cells in O2-deprived settings, we sought to elucidate the role of dual CA IX/XII inhibition as a novel strategy to eliminate AML cells under hypoxic conditions. Our findings demonstrate that the dual CA IX/XII inhibitor FC531 may prove to be of value as an adjunct to chemotherapy for the treatment of AML. |
| Keywords: | acute myeloid leukemia Carbonic Anhydrases drug resistance hypoxia pH regulation |