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
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...
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/3/648 |
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| author | Károly Jambrovics Iván P. Uray Jeffrey W. Keillor László Fésüs Zoltán Balajthy |
| author_facet | Károly Jambrovics Iván P. Uray Jeffrey W. Keillor László Fésüs Zoltán Balajthy |
| author_sort | Károly Jambrovics |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T06:23:35Z |
| format | Article |
| id | doaj.art-0459663cc912454fa5132f1e3bd8726b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:23:35Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0459663cc912454fa5132f1e3bd8726b2023-09-03T02:04:03ZengMDPI AGCancers2072-66942020-03-0112364810.3390/cancers12030648cancers12030648Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2Károly Jambrovics0Iván P. Uray1Jeffrey W. Keillor2László Fésüs3Zoltán Balajthy4Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Clinical Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, CanadaDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryRandomized 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.https://www.mdpi.com/2072-6694/12/3/648acute promyelocytic leukemiaall-trans retinoic acid (atra)arsenic trioxide (ato)atra and ato combination treatmentnb4 |
| spellingShingle | Károly Jambrovics Iván P. Uray Jeffrey W. Keillor László Fésüs Zoltán Balajthy 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 acute promyelocytic leukemia all-trans retinoic acid (atra) arsenic trioxide (ato) atra and ato combination treatment nb4 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | acute promyelocytic leukemia all-trans retinoic acid (atra) arsenic trioxide (ato) atra and ato combination treatment nb4 |
| url | https://www.mdpi.com/2072-6694/12/3/648 |
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