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Abstract
Cisplatin, a widely used chemotherapy for the treatment of various tumors, is clinically limited due to its extensive nephrotoxicity. Inflammatory response in tubular cells is a driving force for cisplatin-induced nephrotoxicity. The plant-derived agents are widely used to relieve cisplatin-induced renal dysfunction in preclinical studies. Polysulfide and hydrogen sulfide (H2S) are ubiquitously expressed in garlic, and both of them are documented as potential agents for preventing and treating inflammatory disorders. This study was designed to determine whether polysulfide and H2S could attenuate cisplatin nephrotoxicity through suppression of inflammatory factors. In renal proximal tubular cells, we found that sodium tetrasulfide (Na2S4), a polysulfide donor, and sodium hydrosulfide (NaHS) and GYY4137, two H2S donors, ameliorated cisplatin-caused renal toxicity through suppression of the massive production of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Mechanistically, the anti-inflammatory actions of Na2S4 and H2S may be mediated by persulfidation of signal transducer and activator of transcription 3 (STAT3) and inhibitor kappa B kinase β (IKKβ), followed by decreased phosphorylation of STAT3 and IKKβ. Moreover, the nuclear translocation of nuclear transcription factor kappa B (NF-κB), and phosphorylation and degradation of nuclear factor kappa B inhibitor protein alpha (IκBα) induced by cisplatin, were also mitigated by both polysulfide and H2S. In mice, after treatment with polysulfide and H2S donors, cisplatin-associated renal dysfunction was strikingly ameliorated, as evidenced by measurement of serum blood urea nitrogen (BUN) and creatinine levels, renal morphology, and the expression of renal inflammatory factors. Our present work suggests that polysulfide and H2S could afford protection against cisplatin nephrotoxicity, possibly via persulfidating STAT3 and IKKβ and inhibiting NF-κB-mediated inflammatory cascade. Our results might shed light on the potential benefits of garlic-derived polysulfide and H2S in chemotherapy-induced renal damage.
Highlights
Cisplatin is a widely used chemotherapeutic agent for the treatment of many solid organ cancers [1]
As renal tubular cell inflammation is closely associated with cisplatin nephrotoxicity (41), the possible roles of exogenous polysulfide and H2S donors in cisplatin-provoked inflammation were examined in renal tubular cells
The results showed that pretreatment with polysulfide donor sodium tetrasulfide (Na2S4), H2S donors sodium hydrosulfide (NaHS), and GYY4137 clearly diminished the upregulated expressions of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-6, and cyclooxygenase-2 (COX-2) in renal tubular cells upon cisplatin challenge, as evidenced by Western blotting and RT-PCR analysis (Figure 1A–C)
Summary
Cisplatin is a widely used chemotherapeutic agent for the treatment of many solid organ cancers [1]. Its clinical application for cancer therapy is largely limited because of its several adverse effects, including ototoxicity, neurotoxicity, and nephrotoxicity [2]. Among these side effects, nephrotoxicity is recognized to be most prevalent: accumulative evidence has revealed that over 30% of subjects might suffer from acute kidney injury after treatment with cisplatin [3]. Acute kidney injury is one of the most frequent complications in cancer patients upon cisplatin treatment [4]. Mitochondrial dysfunction, reactive oxygen species (ROS) formation, caspase activation, and DNA damage are proposed to be involved in the pathologies of cisplatin-triggered acute kidney injury [7]. Anti-inflammatory compounds might serve as adjunctive therapies to prevent and treat cisplatin-related nephrotoxicity
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