article · Frontiers in Pharmacology
Methotrexate is a common chemotherapy agent whose clinical utility is often constrained by kidney damage. In an animal study, oral administration of paeonol, a natural phenolic compound, significantly mitigated methotrexate-induced renal injury. Rats given methotrexate developed impaired kidney function, structural renal damage, oxidative stress, inflammation, and cellular death. Co-treatment with paeonol improved kidney function and structural markers while suppressing oxidative, inflammatory, and apoptotic pathways. Additionally, paeonol upregulated the renal efflux transporter P-glycoprotein, a protein that facilitates methotrexate clearance, without directly inhibiting or acting as a substrate for the transporter. In cell culture tests, paeonol also augmented the cytotoxic effects of methotrexate against colon cancer cells in a dose-dependent manner, suggesting that it can protect kidney tissue while simultaneously supporting anticancer activity.
Methotrexate is an essential cancer treatment, but renal toxicity frequently limits safe dosing and compromises patient outcomes. Identifying natural compounds that reduce kidney damage while preserving or boosting anticancer efficacy is critical. If verified in humans, this approach could help clinicians deliver effective chemotherapy regimens with fewer dose-limiting side effects for oncology patients.
This work represents early-stage laboratory and animal research. If advanced, it could inform the development of protective adjuvant therapies or co-formulated supportive care drugs for pharmaceutical companies producing oncology treatments. Translating these findings into commercial products or clinical practice will require substantial further research, including clinical trials to confirm safety, appropriate dosing, and efficacy in human patients.
AI-generated from the published abstract. Always read the original work before citing.
Methotrexate (MTX) is a well-known anticancer drug that causes nephrotoxicity as a side effect. To investigate the mechanisms by which paeonol, a natural phenolic compound, can protect against MTX-induced nephrotoxicity, paeonol (100 mg/kg/day orally) was given to rats for 10 days, with or without MTX (20 mg/kg once i.p. at day 5). Compared to control, MTX caused nephrotoxic effects manifested by increased serum urea and creatinine and distortion in renal histological architecture, with a significant increase in the mean glomerular diameter and upregulation of kidney injury molecule-1. MTX caused oxidative stress manifested by decreasing reduced glutathione and superoxide dismutase while increasing malondialdehyde and nitric oxide. MTX also induced renal inflammation by upregulating TLR4, NF-κB, and IL-1β and caused apoptosis by induction of caspase 3. Administering paeonol with MTX improved kidney functional and structural parameters, as well as all oxidative, inflammatory, and apoptotic markers tested. Interestingly, both MTX and paeonol increased the expression of the renal efflux transporter P-glycoprotein (P-gp) that helps in MTX elimination, and their drug combination further upregulated renal P-gp. <i>In silico</i>, paeonol was neither a substrate nor an inhibitor of P-gp, suggesting that its effect on P-gp is not on functional but on the expression level. <i>In vitro</i>, paeonol and MTX were administered to colon cancer cells and their combination caused a progressive cellular cytotoxic effect, which was dose-dependent with the increase of paeonol concentration. In conclusion, paeonol protects against MTX-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic mechanisms and might potentiate MTX chemotherapeutic efficacy.
This page summarises published work. The authoritative version sits with the publisher.
DOI: 10.3389/fphar.2022.774387
Is something wrong with this record? Report it or request removal.
Discussion
Have you built on this work, tried to replicate it, or seen it applied in practice? Share what you know. Verified researchers and MARATTO™ domain experts can open a discussion, and any member can reply. Contributions are reviewed before they appear.
No discussion yet. Open the first thread.
New to MARATTO™? Create a free account.
