Auranofin, an Anti-rheumatic Gold Drug, Aggravates the Radiation-Induced Acute Intestinal Injury in Mice

Abstract

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.

Celecoxib, a selective cyclooxygenase-2 inhibitor, aggravates radiation-induced intestinal damage in mice

“…In the present study, we evaluated the role of COX-2 in association with histopathological changes that occur following intestinal irradiation in mice. Previous studies have revealed that intestinal injury after irradiation can be evaluated based on the number of crypts, length of villi, and the size of crypts [10,11,13,15]. The disappearance of intestinal crypts after radiation exposure occurs within 2 days, and a new intestinal shape appears following the recovery of surviving gastrointestinal stem cells 3 to 4 days after irradiation exposure [16].…”

“…The isolated small intestines were fixed in 10% neutral buffered formaldehyde and embedded in paraffin wax to prepare 4-µm-thick jejunal sections for hematoxylin-eosin staining. The regenerating crypts in the jejunal cross-sections were then counted by a previously described microcolony technique [10,11]. The criteria for regenerating crypts is as follow: prominent nucleus, little cytoplasm, lying close together and appearing crowded [12].…”

GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review

“…The orally administrated Auranofin, a carbohydrate-containing gold complex, is used as an antirheumatic agent [286]. Its main MOA is the inhibition of cellular redox enzymes, resulting in enhancement of oxidative stress and intrinsic apoptotic death.…”

The intestinal mucosal barrier – A key player in rheumatoid arthritis?

“…The treatment of RA is based on five categories of drugs: analgetic, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, non-biological and biological disease-modifying anti-rheumatic drugs (DMARDs) (Piovezana Bossolani et al, 2019). These treatments can only temporarily relieve symptoms and may lead to adverse effects such as cardiac complications, ulcers, gastrointestinal damage, and immunosuppression (Lee, Kim, et al, 2019). The intestinal mucosa barrier is a dynamic system that contributes to the stability of the intestinal environment by regulating the absorption of water, electrolytes and nutrients from the lumen into the circulation, while limiting the passage of harmful luminal substances and microorganisms.…”