Diallyl trisulfide and its active metabolite allyl methyl sulfone attenuate cisplatin-induced nephrotoxicity by inhibiting the ROS/MAPK/NF-κB pathway
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Updated: Jul 7, 2025
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Xiaoyan Jiang1, Xiaosong Zhu2, Yan Liu3
1Department of Pharmacy, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China; School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
Abstract:
Cisplatin, a chemotherapy medication employed in the treatment of various solid tumors, is constrained in its clinical application due to nephrotoxicity. Diallyl trisulfide (DATS), a compound derived from garlic that possessed anticancer and antioxidant properties, can be combined with cisplatin without hindering its antitumor effects. The present investigation examined the defensive properties of DATS and its active metabolites against renal dysfunction caused by cisplatin. We created a mouse model to study renal injury caused by cisplatin and assessed kidney histology, immunochemistry, and serum cytokines. DATS treatment effectively reduced the pathological changes caused by cisplatin by decreasing the levels of renal function markers BUN, CRE, cystatin C, NGAL, inflammatory factors TNF-α, IL-6, and the protein expression of α-SMA, NF-κB, KIM-1. A pharmacokinetic evaluation of DATS found that allyl methyl sulfone (AMSO2) was the most abundant and persistent metabolite of DATS in vivo. Then, we examined the impact of AMSO2 on cell viability, apoptosis, ROS generation, and MAPK/NF-κB pathways in HK-2 cells treated with cisplatin. Cotreatment with AMSO2 effectively hindered the HK-2 cells alterations induced by cisplatin. Furthermore, AMSO2 mitigated oxidative stress through the modulation of MAPK and NF-κB pathways. Our findings indicated that DATS and its active derivative AMSO2 attenuated cisplatin-induced nephrotoxicity. DATS shows potential as a viable treatment for nephrotoxicity caused by cisplatin.
Insights
Diallyl trisulfide (DATS), a garlic compound, protects against cisplatin-induced kidney damage. Its metabolite, allyl methyl sulfone (AMSO2), also shows protective effects, offering potential for managing chemotherapy side effects.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- Cisplatin is a vital chemotherapy drug but causes significant nephrotoxicity, limiting its use.
- Diallyl trisulfide (DATS), a garlic-derived compound, exhibits anticancer and antioxidant properties.
- DATS can be combined with cisplatin without compromising its anti-tumor efficacy.
Purpose of the Study:
- To investigate the protective effects of DATS and its metabolites against cisplatin-induced nephrotoxicity.
- To identify the primary active metabolite of DATS in vivo and evaluate its renoprotective potential.
- To elucidate the molecular mechanisms underlying the protective actions of DATS and its metabolite.
Main Methods:
- A mouse model of cisplatin-induced renal injury was established.
- Kidney histology, serum cytokine levels, and renal function markers were assessed.
- Pharmacokinetic analysis identified DATS metabolites, and in vitro studies used HK-2 cells to assess AMSO2's effects on cisplatin-induced damage.
Main Results:
- DATS treatment significantly reduced cisplatin-induced pathological changes and markers of kidney dysfunction (BUN, CRE, cystatin C, NGAL).
- DATS decreased inflammatory factors (TNF-α, IL-6) and expression of α-SMA, NF-κB, and KIM-1.
- Allyl methyl sulfone (AMSO2) was identified as the most abundant and persistent DATS metabolite, which protected HK-2 cells from cisplatin-induced alterations by modulating MAPK and NF-κB pathways.
Conclusions:
- DATS and its active metabolite AMSO2 effectively attenuate cisplatin-induced nephrotoxicity.
- DATS demonstrates potential as a therapeutic agent to mitigate cisplatin-related kidney damage.
- Targeting oxidative stress and inflammatory pathways via DATS/AMSO2 offers a promising strategy for managing chemotherapy side effects.
