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Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2

1
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
2
Department of Clinical Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
3
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
4
MTA DE Apoptosis, Genomics and Stem Cell Research Group of the Hungarian Academy of Sciences, 4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 648; https://doi.org/10.3390/cancers12030648
Received: 2 February 2020 / Revised: 6 March 2020 / Accepted: 9 March 2020 / Published: 11 March 2020
(This article belongs to the Special Issue Acute Promyelocytic Leukemia)
Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA- and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1β] and tumor necrosis factor-α [TNF-α]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expression-dependent manner. The amount of secreted TNF-α in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1β and TNF-α 8-, 15- and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome. View Full-Text
Keywords: acute promyelocytic leukemia; all-trans retinoic acid (ATRA); arsenic trioxide (ATO); ATRA and ATO combination treatment; NB4 acute promyelocytic leukemia; all-trans retinoic acid (ATRA); arsenic trioxide (ATO); ATRA and ATO combination treatment; NB4
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Jambrovics, K.; Uray, I.P.; Keillor, J.W.; Fésüs, L.; Balajthy, Z. Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2. Cancers 2020, 12, 648.

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