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Upadacitinib protects against cisplatin-induced renal and hepatic dysfunction without impairing its anticancer

Hanan S Anbar1, Naglaa G Shehab2, Nadia M M El-Rouby3

  • 1Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai 19099, United Arab Emirates.

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
|February 21, 2022
PubMed

Insights

Upadacitinib, a JAK1 inhibitor, protects against cisplatin-induced kidney and liver damage by reducing inflammation and oxidative stress. Importantly, it enhances cisplatin

Area of Science:

  • Pharmacology
  • Toxicology
  • Oncology

Background:

  • Cisplatin is a widely used chemotherapy agent, but its clinical application is limited by significant renal and hepatic toxicities.
  • Inflammation plays a key role in the molecular mechanisms underlying cisplatin-induced organ damage.

Purpose of the Study:

  • To investigate the protective effects of upadacitinib, a selective JAK1 inhibitor, against cisplatin-induced nephrotoxicity and hepatotoxicity in male Wistar rats.
  • To evaluate the impact of upadacitinib on inflammatory biomarkers, oxidative stress, and histopathological changes.
  • To assess whether upadacitinib affects cisplatin's anticancer efficacy.

Main Methods:

  • Male Wistar rats were pre-treated with upadacitinib (10 mg/kg/day) for two weeks before a single dose of cisplatin (10 mg/kg).
  • Liver and kidney functions, oxidative stress markers (MDA, SOD), and inflammatory biomarkers (TNFα) were biochemically assessed.
  • Histopathological examination of liver and kidney tissues was performed.
  • Western blotting was used to analyze NF-kB and p-Akt expression.
  • Cell viability assays were conducted using MCF-7 and A549 cancer cell lines.

Main Results:

  • Upadacitinib significantly improved liver function markers (ALT, AST) and lipid profiles, and protected kidney function (BUN, creatinine, albumin).
  • It attenuated cisplatin-induced hepatic and renal inflammation (reduced MDA, TNFα) and enhanced antioxidant activity (increased SOD).
  • Histopathological damage in liver and kidney tissues was diminished, supported by Western blot data showing modulation of NF-kB and p-Akt.
  • Upadacitinib did not inhibit cisplatin's anticancer activity and even enhanced its potency against lung cancer cells in vitro.

Conclusions:

  • Upadacitinib demonstrates significant renoprotective and hepatoprotective effects against cisplatin-induced toxicity in rats.
  • These protective effects are mediated through the inhibition of inflammatory pathways and oxidative stress.
  • Upadacitinib can be a valuable adjunct therapy, offering organ protection without compromising cisplatin's anticancer efficacy.
Keywords:
CisplatinHepatotoxicityJAK InhibitorNephrotoxicityOxidative stressUpadacitinib

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