Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway
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Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity.
Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity.
This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation.
Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3 weeks; Group 2 (CFZ/toxic group) received CFZ [4 mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3 weeks; Group 3 (standard treatment group) was administered CFZ (4 mg/kg, i.p.) and olmesartan (2 mg/kg, p.o.) for 3 weeks; Group 4 was administered CFZ (4 mg/kg, i.p.) and rutin (10 mg/kg, p.o.) for 3 weeks; Group 5 was administered CFZ (4 mg/kg, i.p.) and rutin (20 mg/kg, p.o.) for 3 weeks; and Group 6 was administered CFZ (4 mg/kg, i.p.) and rutin (40 mg/kg, p.o.) for 3 weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration.
Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity.
These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.
KeywordsRutin Carfilzomib Nephrotoxicity NOS-2 NF-κB Histopathology
Analysis of variance
Blood urea nitrogen
Food and Drug Application
Glomerular filtration rate
Hematoxylin and eosin
Inhibitory kappa-B alpha
Nicotinamide adenine dinucleotide phosphate
Nuclear factor kappa-B
Nitric oxide synthase
Red blood cells
Ras homolog gene family, member A
Rho-associated kinase (rho-kinase)
Standard error of mean
Transforming growth factors
White blood cells
The present work was funded by King Saud University, Deanship of Scientific Research, College of Pharmacy (project no. RGP-VPP-305). The authors would like to thank the Department of Pharmacology and Toxicology at the College of Pharmacy, King Saud University for granting us permission to use its facilities.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
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