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Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells.

ABSTRACT: Patients with chronic myeloid leukemia (CML) are commonly treated with a specific inhibitor of BCR-ABL tyrosine kinase, imatinib mesylate (IM). Unfortunately, CML patients develop IM-resistance, which has emerged as a significant clinical problem. Somatic mutations, especially T315I mutation, in BCR-ABL kinase domain represent the most common mechanism underlying drug resistance to tyrosine kinase inhibitors (TKI), including imatinib. Thus, it is urgent to develop novel therapeutic strategies to overcome TKI-resistance. The anti-rheumatic gold (I) compound Auranofin (AF), was recently approved by US Food and Drug Administration for Phase II clinical trials to treat leukemia. In a recent study, we discovered that AF can selectively inhibit 19S proteasome-associated deubiquitinases (UCHL5 and USP14), which mediates its anticancer effects. More recently studies we have shown that AF inhibits the growth of both Bcr-Abl wild-type cells and IM-resistant Bcr-Abl-T315I mutation cells in vitro and in vivo. AF-induced Bcr-Abl down regulation is associated with diminished mRNA expression and caspase-dependent Bcr-Abl cleavage. More importantly, we unraveled that AF cytotoxicity is mediated by proteasome inhibition rather than previously suspected reactive oxygen species (ROS) generation. These findings support that AF overcomes IM-resistance through Bcr/Abl-dependent and -independent mechanisms, identifying a potentially new strategy for cancer treatment.

SUBMITTER: Chen X

PROVIDER: S-EPMC4434598 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells.

Chen Xin X Shi Xianping X Wang Xuejun X Liu Jinbao J

Cancer cell & microenvironment 20141101 6

Patients with chronic myeloid leukemia (CML) are commonly treated with a specific inhibitor of BCR-ABL tyrosine kinase, imatinib mesylate (IM). Unfortunately, CML patients develop IM-resistance, which has emerged as a significant clinical problem. Somatic mutations, especially T315I mutation, in BCR-ABL kinase domain represent the most common mechanism underlying drug resistance to tyrosine kinase inhibitors (TKI), including imatinib. Thus, it is urgent to develop novel therapeutic strategies to ...[more]

PMID: 25995993

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Project description:Pelvic and abdominal radiotherapy plays an important role in eradication of malignant cells; however, it also results in slight intestinal injury. The apoptosis of cells in the intestinal epithelium is a primary pathological factor that initiates radiation-induced intestinal injury. Auranofin, a gold-containing triethylphosphine, was approved for the treatment of rheumatoid arthritis, and its therapeutic application has been expanded to a number of other diseases, such as parasitic infections, neurodegenerative disorders, AIDS, and bacterial infections. Recently, a treatment strategy combining the use of auranofin and ionizing radiation aimed at increasing the radiosensitivity of cancer cells was proposed for improving the control of local cancers. In this study, we evaluated the effect of auranofin on the radiosensitivity of intestinal epithelial cells. The treatment with a combination of 1 μM auranofin and 5 Gy ionizing radiation showed clear additive effects on caspase 3 cleavage and apoptotic DNA fragmentation in IEC-6 cells, and auranofin administration significantly aggravated the radiation-induced intestinal injury in mice. Auranofin treatment also resulted in the activation of the unfolded protein response and in the inhibition of thioredoxin reductase, which is a key component of the cellular antioxidant system. Pre-treatment with N-acetyl cysteine, a well-known scavenger of reactive oxygen species, but not with a chemical chaperone, which inhibits endoplasmic reticulum stress and the ensuing unfolded protein response, significantly reduced the radiosensitizing effects of auranofin in the IEC-6 cells. In addition, transfection of IEC-6 cells with a small interfering RNA targeted against thioredoxin reductase significantly enhanced the radiosensitivity of these cells. These results suggest that auranofin-induced radiosensitization of intestinal epithelial cells is mediated through oxidative stress caused by the deregulation of thioredoxin redox system, and auranofin treatment can be an independent risk factor for the development of acute pelvic radiation disease.

Dataset Information

Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells.

Publications

Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells.

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