Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells
| Autor: | Milena Botelho Pereira Soares, Ludmila de Faro Valverde, Hector H. F. Koolen, Emmanoel V. Costa, Daniel P. Bezerra, Rosane Borges Dias, Clarissa Araújo Gurgel Rocha, Felipe M. A. da Silva, Larissa M. Bomfim, Ana Carolina B. da C. Rodrigues, Waldireny Caldas Rocha, Sara P. Neves |
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| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
MAP Kinase Signaling System p38 mitogen-activated protein kinases Down-Regulation Apoptosis HL-60 Cells RM1-950 p38 Mitogen-Activated Protein Kinases Antioxidants Cell Line Tingenone Mice Thioredoxins AML Salacia 22-hydroxytingenone Cell Line Tumor Animals Humans DNA Breaks Double-Stranded Fragmentation (cell biology) Thioredoxin Pharmacology Chemistry Cell growth Myeloid leukemia General Medicine Molecular biology Antineoplastic Agents Phytogenic Triterpenes Leukemia Myeloid Acute Oxidative Stress Cancer cell Therapeutics. Pharmacology |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 142, Iss, Pp 112034-(2021) |
| ISSN: | 1950-6007 |
| Popis: | Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin. |
| Databáze: | OpenAIRE |
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