The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin

Abstract

Purpose UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. Materials and Methods BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg respectively on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and bodyweights were monitored. Results UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150% of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200% of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight-loss induced by cisplatin indicating that bodyweight may not be a sensitive enough measure for chemoprotection of UTL-5g against cisplatin. Conclusions In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.

Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation

“…UTL-5g is a chemoprotective agent (Shaw et al, 2010; Shaw et al, 2013) that eases the chemotherapy-induced inflammation that can limit the dose and duration of treatment. We previously reported that UTL-5g blocks LPS-stimulated PGE2 production in the mouse RAW 264.7 cell line (Shaw, 2015) validating LPS treated RAW 264.7 cells as a model system for investigating the mechanism for UTL-5g anti-inflammatory activity.…”

“…For example, UTL-5g reduces cisplatin-induced toxicity by protecting kidney, liver, and platelets, thereby increasing the tolerance of mice for cisplatin (Shaw et al, 2013). UTL-5g increases the survival rates of mice treated with lipopolysaccharide (LPS) (Zhang et al, 2014) and reduces radiation-induced liver damage (Shaw et al, 2012).…”

Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats

“…TNF-α and its superfamily members are known to have both beneficial and harmful effects. The increased production of ROS can accelerate the expression of nuclear factor kappa B and proinflammatory cytokines such as TNF-α and IL-6, which could increase the cytotoxic effects of Cis in liver tissues (22). A previous study has shown that UTL-5g-a novel small-molecule TNF-α inhibitor protects the liver from Cis-induced hepatotoxicity, as indicated by lowering the elevated levels of AST, ALT, and TNF-α (23).…”

UTL-5g Lowers Elevated Blood Levels of TNF-a and TGF-? and Increases Survival Rates in Animals Treated with LPS/D-(+)-galactosamine

“…However, UTL-5 compounds possess some protective effects which are significantly different from those of leflunomide. For example, UTL-5g reduces cisplatin-induced side effects by protecting kidney, liver, and platelets [6], thereby, increasing the tolerability of cisplatin [15]. In addition, UTL-5b and -5g reduce radiation-induced side effects in liver [16].…”