Protective potential of Irosustat, STX140 and the sulfonate derivative 1G in counteracting cisplatin-induced renal and hepatic toxicities: An in vivo comparative study.

Cisplatin, a widely used chemotherapeutic agent, is often limited by its nephrotoxic and hepatotoxic effects, largely driven by oxidative stress and inflammation. This study evaluates the protective effects of irosustat, the steroidal bis-sulfamate STX140, and a sulfonate derivative (1G) against cisplatin-induced organ toxicity in a rat model, with silymarin and losartan as reference standards. Male Wistar rats (n = 5/group) received daily oral doses of the test compounds for two weeks, with a single intraperitoneal cisplatin injection (10 mg/kg) on day 7 to induce toxicity. Biochemical, histopathological, and molecular analyses assessed renal and hepatic function, oxidative stress markers, and inflammatory mediators (TNF-α, Nrf-2, Hmox-1, NF-kb1, and IL-6) via qRT-PCR and immunohistochemistry. Pre-treatment with each compound improved kidney and liver function, as evidenced by significant reductions in serum creatinine and blood urea nitrogen levels, and restoration of serum albumin levels. Oxidative stress and inflammatory markers were downregulated, correlating with histopathological improvements in renal and hepatic tissues. Notably, STX140 co-treatment may have reduced the IC50 of cisplatin in A549 and MCF7 cancer cell lines, suggesting the possibility of a sensitizing effect, but with the caveat that STX140 is itself a much more potent agent. These findings highlight irosustat, STX140, and 1G as promising candidates for attenuating cisplatin-induced organ toxicity without compromising its anticancer efficacy. However, further investigations are required to elucidate the precise molecular mechanisms, optimize synergistic dosing strategies, and assess long-term safety in preclinical models.