Therapeutic Effect of GGsTop, Selective Gamma-glutamyl Transpeptidase Inhibitor, on a Mouse Model of 5-Fluorouracil-induced Oral Mucositis

Abstract

Background: Oral mucositis (OM) induced by cancer chemotherapy has a high incidence and serious symptoms, which often force chemotherapy to be stopped. GGsTop is a newly-discovered gamma-glutamyl transpeptidase (GGT) inhibitor. Previous research suggested that inhibition of GGT suppressed reactive oxygen species and induced the production of collagen and elastin. We hypothesized that GGsTop could safely treat OM. Materials and Methods: A mouse model of OM was treated with GGsTop and ulcer area, weight, and white blood cell count were determined. The treatment effect was also evaluated by hematoxylin-eosin and collagen staining. Results: The therapeutic effect of GGsTop was better than that of an existing drug and may be safely used in combination with chemotherapy. Furthermore, GGsTop promoted collagen production in oral mucosa. Conclusion: GGsTop treated OM quickly and safely. GGsTop is highly valuable for use as a treatment for OM.Oral mucositis (OM), one of the side-effects induced by chemotherapy, has reported incidence of 40%, increasing to approximately 100% for chemotherapy in combination with radiotherapy (1, 2). OM caused by anticancer drug treatment is shown as erythema, edema or ulceration that can be accompanied by alterations ranging from mild burning sensation to large and painful ulcers and has a wider range of presentations than general stomatitis (3, 4). Symptoms include eating disorders, communication obstacles, and sleep disorders as well as the sharp pain, which reduce the patients' quality of life (QOL) (5). Loss of consciousness was also reported to occur as a result of deterioration of OM which forced the treatment to stop (6). Preventing OM or treating it quickly brings improvement of QOL, and reduces the need for treatment interruption. At present, various treatments (oral cryotherapy, brushing, administration of steroidal antiinflammatory drug, disinfectant mouthwash, etc.) are performed (5, 7). However, they do not seem to bring enough relief nor preventive effect (8). A novel drug for OM is needed.Anticancer drugs cause stomatitis mainly by two methods. One is by direct mucosal injury and the other is indirectly by causing a bacterial infection in the oral mucosa (9). Previous research reported that since the cell cycle of oral mucosal cells is as short as that of cancer cells, oral mucosal cells were damaged by anticancer drugs. In addition, reactive oxygen species (ROS) generated by anticancer drugs cause mucosal damage (10). It is also reported that bacterial infection is due to immunosuppression by anticancer agents, reduced mucus secretion, a decrease in the number of mucosal cells, and reduced barrier function (10). Because of these characteristics, it is impossible to use existing medicine for stomatitis, which mainly comprises steroidal anti-inflammatory drugs (11). This fact is a major cause for stomatitis during cancer chemotherapy and is regarded as a problem.Gamma-glutamyl transpeptidase (GGT) is a highly glycosylated heterodimeric enzyme that is widely found in organisms f...

Sulfur-containing histidine compounds inhibit γ-glutamyl transpeptidase activity in human cancer cells

“…However, most of these compounds have proved to be toxic (20 -22) due to their interference with essential pathways such as the glutamate recycling involved in neurotransmission. Among monophenyl phosphonoglutamate analogues, only the butanoic acid derivative GGsTop was found to be inactive on glutamine amidotransferase (23) and effective for the treatment of oral mucositis (24). In contrast, serine borate was found to be too weak as inhibitor (16,25).…”

Inhibition of γ‐glutamyltransferase ameliorates ischaemia‐reoxygenation tissue damage in rats with hepatic steatosis

“…X‐ray crystallography with Escherichia coli γ‐GT, sequence alignment and site‐directed mutagenesis of human γ‐GT revealed a critical electrostatic interaction between the terminal carboxylate of GGsTop and the active‐site residue Lys562 of human γ‐GT for potent inhibition (Kamiyama et al, 2016). GGsTop promoted collagen production in oral mucosa and has therapeutic effects on oral mucositis (Shimamura, Takeuchi, Terada, & Makino, 2019). It was reported that inhibition of γ‐GT activity in lung lining fluid increased GSH levels and protected lung airway epithelial cells against oxidative stress injury and associated inflammation in a mouse of model of asthma and recommended GGsTop as a novel pharmacological agent for the treatment of asthma (Tuzova et al, 2014).…”

“…GGsTop promoted collagen production in oral mucosa and has therapeutic effects on oral mucositis (Shimamura, Takeuchi, Terada, & Makino, 2019). It was reported that inhibition of γ-GT activity in lung lining fluid increased GSH levels and protected lung airway epithelial cells against oxidative stress injury and associated inflammation in a mouse of model of asthma and recommended GGsTop as a novel pharmacological agent for the treatment of asthma (Tuzova et al, 2014).…”

Probing the Interactions of Sulfur-Containing Histidine Compounds with Human Gamma-Glutamyl Transpeptidase

“…Glutamine analogues have been developed, acting as irreversible competitive inhibitors due to their binding affinity for the donor site, but most of them have been abandoned in clinical trials due to toxicity [30][31][32]. Glutamic acid/glutamate derivatives have been proven to provide a valid therapeutic alternative, as these irreversible GGT inhibitors are more selective and less toxic [33][34][35][36][37]. Finally, a novel class of uncompetitive inhibitors has also been identified, whose action is displayed by binding to the acceptor site of the enzyme, thus resulting in less toxicity compared to the glutamine analogues [38].…”

“…For example, a butanoic acid derivative (GGsTop) was found to be effective for the treatment of ischemia/reperfusion-induced renal injury, asthma, and oral mucositis [26,27,37]. Moreover, a class of uncompetitive inhibitors, which bind the acceptor site and are less toxic than glutamine analogues, have been developed, but no further in vitro and in vivo studies have confirmed their therapeutic potential [38].…”