Inhibition of thioredoxin-dependent H2O2 removal sensitizes malignant B-cells to pharmacological ascorbate
Agnieszka Graczyk-Jarzynka,
Agnieszka Goral,
Angelika Muchowicz,
Radoslaw Zagozdzon,
Magdalena Winiarska,
Malgorzata Bajor,
Anna Trzeciecka,
Klaudyna Fidyt,
Joanna Alicja Krupka,
Julia Cyran,
Kacper Szczygiel,
Dimitar G. Efremov,
Stefania Gobessi,
Adam Jagielski,
Karolina Siudakowska,
Malgorzata Bobrowicz,
Marta Klopotowska,
Joanna Barankiewicz,
Agata Malenda,
Ewa Lech-Maranda,
Nina Miazek-Zapala,
Piotr Henryk Skarzynski,
Antoni Domagala,
Jakub Golab,
Malgorzata Firczuk
Affiliations
Agnieszka Graczyk-Jarzynka
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Agnieszka Goral
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Angelika Muchowicz
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Radoslaw Zagozdzon
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka 59 Street, 02-006 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5 A Street, 02-106 Warsaw, Poland
Magdalena Winiarska
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Malgorzata Bajor
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Anna Trzeciecka
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Klaudyna Fidyt
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Zwirki i Wigury 61 Street, 02-091 Warsaw, Poland
Joanna Alicja Krupka
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Julia Cyran
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Kacper Szczygiel
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Dimitar G. Efremov
Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Località Padriciano 99 Street, 34149 Trieste, Italy
Stefania Gobessi
Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Località Padriciano 99 Street, 34149 Trieste, Italy
Adam Jagielski
Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Miecznikowa 1 Street, 02-096 Warsaw, Poland
Karolina Siudakowska
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Malgorzata Bobrowicz
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Marta Klopotowska
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Zwirki i Wigury 61 Street, 02-091 Warsaw, Poland
Joanna Barankiewicz
Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland; Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medicine, Marymoncka 99/103 Street, 01-813 Warsaw, Poland
Agata Malenda
Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland
Ewa Lech-Maranda
Department of Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Street, 02-776 Warsaw, Poland; Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medicine, Marymoncka 99/103 Street, 01-813 Warsaw, Poland
Nina Miazek-Zapala
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Institute of Physiology and Pathology of Hearing, World Hearing Center, Mochnackiego 10 Street, 02-042 Warsaw, Poland
Piotr Henryk Skarzynski
Institute of Physiology and Pathology of Hearing, World Hearing Center, Mochnackiego 10 Street, 02-042 Warsaw, Poland; Institute of Sensory Organs, Mokra 17 Street, 05-830 Kajetany, Poland; Department of Heart Failure and Cardiac Rehabilitation, Medical University of Warsaw, Kondratowicza 8 Street, 03-242 Warsaw, Poland
Antoni Domagala
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland
Jakub Golab
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Centre for Preclinical Research and Technology, Medical University of Warsaw, Zwirki I Wigury 81 Street, 02-091 Warsaw, Poland; Corresponding author.
Malgorzata Firczuk
Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland; Corresponding author at: Department of Immunology, Medical University of Warsaw, Nielubowicza 5 Street, 02-097 Warsaw, Poland.
L-ascorbate (L-ASC) is a widely-known dietary nutrient which holds promising potential in cancer therapy when given parenterally at high doses. The anticancer effects of L-ASC involve its autoxidation and generation of H2O2, which is selectively toxic to malignant cells. Here we present that thioredoxin antioxidant system plays a key role in the scavenging of extracellularly-generated H2O2 in malignant B-cells. We show that inhibition of peroxiredoxin 1, the enzyme that removes H2O2 in a thioredoxin system-dependent manner, increases the sensitivity of malignant B-cells to L-ASC. Moreover, we demonstrate that auranofin (AUR), the inhibitor of the thioredoxin system that is used as an antirheumatic drug, diminishes the H2O2-scavenging capacity of malignant B-cells and potentiates pharmacological ascorbate anticancer activity in vitro and in vivo. The addition of AUR to L-ASC-treated cells triggers the accumulation of H2O2 in the cells, which results in iron-dependent cytotoxicity. Importantly, the synergistic effects are observed at as low as 200 µM L-ASC concentrations. In conclusion, we observed strong, synergistic, cancer-selective interaction between L-ASC and auranofin. Since both of these agents are available in clinical practice, our findings support further investigations of the efficacy of pharmacological ascorbate in combination with auranofin in preclinical and clinical settings.
