Abstract
Aims: Cyclophosphamide (CP) is a broad-spectrum chemotherapy agent available to treat various malignancies; however, its nephrotoxicity limits its clinical use. Formononetin (FOR) is a bioactive isoflavone with encouraging biological activities. The current study explored and elucidated the possible protective/therapeutic effects of formononetin against CP-induced nephrotoxicity.
 Methodology: Rats received FOR (40 mg/kg/day) for 15 days followed by a single injection of CP on day 16. CP-induced nephrotoxicity is characterized by an increase in urea and creatinine levels in serum. Kidney homogenate was used to assess MDA, NO and antioxidants.
 Results: CP-administered rats showed increased renal malondialdehyde and nitric oxide along with declined glutathione and antioxidant enzymes. In addition, CP increased pro-inflammatory cytokines and pro-apoptotic proteins levels and decreased anti-apoptotic protein Bcl2 levels in the kidney. FOR prevented CP-induced kidney injury, enhanced antioxidants and suppressed oxidative stress, pro-inflammatory mediators and apoptosis.
 Conclusion: These findings suggest that FOR prevents CP nephrotoxicity by attenuating the oxidative damage and inflammation. Therefore, our data suggest that FOR may represent a novel protective strategy against CP-induced nephrotoxicity, which deserves pursuit in further studies.
Highlights
Cyclophosphamide (CP), an alkylating agent, is one of the most potent chemotherapeutic agents used to treat various human malignant tumors [1,2]
Some limitations have been made on its clinical application due to its nephrotoxicity, which restricts the usage of high doses to maximize the therapeutic efficacy [3,4,5]
Since oxidative stress plays a key role in the development of CP nephrotoxicity, mitigating oxidative stress and inflammation may protect against drugs-induced nephrotoxicity
Summary
Cyclophosphamide (CP), an alkylating agent, is one of the most potent chemotherapeutic agents used to treat various human malignant tumors [1,2]. ROS result in lipid peroxidation, protein carbonylation and oxidative DNA damage [7,8], and that might lead to activation of multiple signaling nephrotoxicity pathways including proinflammatory cytokines [5,9], thereby amplifying the inflammatory cascade and eventually culminating in cell death. It is well-known that oxidative stress and inflammation play key roles in the activation of apoptotic signaling pathways in the kidney, which include mitochondrialdependent caspase pathway [6]. Since oxidative stress plays a key role in the development of CP nephrotoxicity, mitigating oxidative stress and inflammation may protect against drugs-induced nephrotoxicity
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