Lactoferrin ameliorates carfilzomib-induced renal and pulmonary deficits: Insights to the inflammasome NLRP3/NF-κB and PI3K/Akt/GSK-3β/MAPK axes

Carfilzomib, an irreversible proteasome inhibitor, has been increasingly used to treat multiple myeloma worldwide. However, case studies showed its treatment has been associated with cardiac, renal, and pulmonary deleterious effects. Lactoferrin is an iron-binding glycoprotein present in milk. It is a multifunctional protein with antimicrobial activity, antitumor, antioxidant, and anti-inflammatory effects. Thus, this study aimed to assess the protective effects of lactoferrin against carfilzomib-induced nephrotoxicity and pulmonary toxicity, in addition to identifying the possible underlying molecular mechanisms. Mice were treated with lactoferrin (300 mg/kg/day) concomitantly with carfilzomib (4 mg/kg, i.p.) twice weekly for three weeks. Kidney and lung indices, serum creatinine, blood urea nitrogen (BUN), uric acid, kidney injury molecule-1 (KIM-1), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and histological examination were assessed. In addition, biochemical analyses of the inflammasome NLRP3/NF-κB and PI3K/Akt/GSK-3β/MAPK axes were conducted. Treatment with lactoferrin decreased serum levels of creatinine, BUN, uric acid, KIM-1, ALP, AST, and LDH and reversed carfilzomib-induced histological changes in both kidney and lung. The inflammatory markers NLRP3, p65 NF-kB, caspases1, interleukin-1β, and interleukin-18, as well as the MAPK signaling pathway, were significantly reduced in renal and pulmonary tissues of mice following lactoferrin administration. Moreover, lactoferrin significantly counteracted carfilzomib-induced reduced expression of pAkt and pGSK-3β in both renal and pulmonary tissues. The current study suggests lactoferrin might be a promising candidate for ameliorating carfilzomib-induced nephrotoxicity and pulmonary toxicity.