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Chrysophanol Relieves Cisplatin-Induced Nephrotoxicity via Concomitant Inhibition of Oxidative Stress, Apoptosis, and Inflammation.

ABSTRACT: Cisplatin (CDDP) is one of the most frequently prescribed chemotherapy medications. However, its nephrotoxicity which often leads to acute kidney injury (AKI), greatly limits its clinical application. Chrysophanol (CHR), a mainly active anthraquinone ingredient, possesses various biological and pharmacological activities. In this study, we aimed to investigate the underlying protective mechanisms of CHR against CDDP-induced AKI (CDDP-AKI) using C57BL/6 mouse and human proximal tubule epithelial cells. In vivo, we found that pre-treatment with CHR greatly relieved CDDP-AKI and improved the kidney function and morphology. The mechanistic studies indicated that it might alleviate CDDP-AKI by inhibiting oxidative stress, apoptosis, and IKKβ/IκBα/p65/transcription factor nuclear kappa B (NF-κB) inflammation signaling pathway induced by CDDP. Moreover, we found that the cell viability of HK2 cells reduced by CDDP was partially rescued by CHR pre-incubation. Flow cytometry results further indicated that CHR pre-incubation suppressed CDDP induced cellular reactive oxygen species (ROS) generation and inhibited cell apoptosis in a dose-dependent manner. In summary, our results suggested that CHR might be a novel therapy for CDDP-induced AKI.

SUBMITTER: Ma S

PROVIDER: S-EPMC8514135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cisplatin (CP) is one of the most effective antitumor drugs in the clinic, but has serious adverse reactions, and its hepatotoxicity has not been fully investigated. Licorice (GC), a traditional herbal medicine, has been commonly used as a detoxifier for poisons and drugs, and may be an effective drug for CP-induced hepatotoxicity. However, its mechanism and the effector molecules remain ambiguous. Therefore, in this study, a network pharmacology and proteomics-based approach was established, and a panoramic view of the detoxification of GC on CP-induced hepatotoxicity was provided. The experimental results indicated that GC can recover functional indices and pathological liver injury, inhibit hepatocyte apoptosis, upregulate B-cell lymphoma/leukemia 2 (Bcl-2) and superoxide dismutase (SOD) levels, and downregulate cellular tumor antigen p53 (p53), caspase-3, malondialdehyde (MDA), high mobility group protein B1 (HMGB1), tumor necrosis factor alpha (TNF-α), and interleukin 1β (IL-1β) levels. Proteomics indicated that GC regulates phosphatidylcholine translocator ABCB1 (ABCB1B), canalicular multispecific organic anion transporter 1 (ABCC2), cytochrome P450 4A2 (CYP4A2), cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2), estrogen receptor (ESR1), and DNA topoisomerase 2-alpha (TOP2A), inhibits oxidative stress, apoptosis, and inflammatory responses, and accelerates drug metabolism. In this study, we provide the investigation of the efficacy of GC against CP-induced hepatotoxicity, and offers a promising alternative for the clinic.

2020-11-27 | PXD021688 | Pride

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Project description:Cisplatin is a highly effective chemotherapeutic drug used to treat a wide variety of solid tumors. However, its use was limited due its dose-limiting toxicity to the kidney. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Honey is a naturally occurring complex liquid and widely used in traditional Ayurvedic medicine to treat many illnesses. However, its effect on cisplatin nephrotoxicity is unknown. To determine the role of honey in cisplatin nephrotoxicity, animals were pretreated orally for a week and then cisplatin was administered. Honey feeding was continued for another 3 days. Our results show that animals with cisplatin-induced kidney dysfunction, as determined by increased serum creatinine, which received honey feeding had less kidney dysfunction. Improved kidney function was associated with better preservation of kidney morphology in honey-treated group as compared to the cisplatin alone-treated group. Interestingly, honey feeding significantly reduced cisplatin-induced tubular epithelial cell death, immune infiltration into the kidney as well as cytokine and chemokine expression and excretion as compared to cisplatin treated animals. Western blot analysis shows that cisplatin-induced increase in phosphorylation of NFkB was completely suppressed with honey feeding. In conclusion, honey feeding protects the kidney against cisplatin nephrotoxicity through suppression of inflammation and NFkB activation.

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