Open AccessPharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions
Author(s) -
Chen Fangli,
Licarete Emilia,
Wu Xue,
Petrusca Daniela,
Maguire Callista,
Jacobsen Max,
Colter Austyn,
Sandusky George E.,
Czader Magdalena,
Capitano Maegan L.,
Ropa James P.,
Boswell H. Scott,
Carta Fabrizio,
Supuran Claudiu T.,
Parkin Brian,
Fishel Melissa L.,
Konig Heiko
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.17027
Subject(s) - cancer research , cd33 , myeloid , bone marrow , myeloid leukemia , biology , chemotherapy , immunology , medicine , microbiology and biotechnology , stem cell , cd34
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 (O 2 )‐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 O 2 ‐deprived milieu. CA IX and XII function as transmembrane proteins that mediate intracellular pH under low O 2 conditions. Because maintaining a neutral pH represents a key survival mechanism for tumour cells in O 2 ‐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.