Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100% to baseline) in CDDP-treated patients was -9.2%, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (≥50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35% of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity.

Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.

Whether there is a mechanistic link between FOLR1 and response to cisplatin has not been extensively examined. In this study, we determine the expression of FOLR1 in ovarian cancer and examine if FOLR1 levels influence response to cisplatin.

Cisplatin-based chemotherapy is the foundation of treatment for major non-small cell lung cancer (NSCLC) patients. However, cisplatin resistance is still a challenging issue, and the molecular mechanisms underlying this resistance remain to be fully explored. CLEC4M, a Ca2+-dependent C-type lectin, has recently been found to correlate with tumourigenesis. This study mainly focused on whether CLEC4M impacts clinical prognosis and how CLEC4M contributes to cisplatin resistance in NSCLC. Our results found that CLEC4M was correlated with poor prognosis in patients with lung cancer. In addition, a positive association between CLEC4M expression and the IC50 values of cisplatin was found, which suggests that CLEC4M may impact cisplatin sensitivity. In vitro results from cultured A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown led to higher sensitivity to cisplatin in these cells. Further experiments showed that the underlying mechanisms included inhibition of cisplatin-induced cell apoptosis by CLEC4M and improved DNA repair capacity by upregulating XPA and ERCC1 expression. In addition, CLEC4M was able to promote cell migration with or without cisplatin treatment. Collectively, these findings suggest the potential clinical significance of CLEC4M inhibition in overcoming cisplatin resistance in NSCLC patients.

Recently, autophagy has been indicated to play an essential role in various biological events, such as the response of cervical cancer cells to chemotherapy. However, the exact signalling mechanism that regulates autophagy during chemotherapy remains unclear. In the present study, we investigated the regulation by cisplatin on protein kinase C β (PKC β), on B-cell lymphoma 2 (Bcl-2) and on apoptosis in cervical cancer Hela cells. And then we examined the regulation by cisplatin on autophagy and the role of autophagy on the chemotherapy in Hela cells. In addition, the regulation of the PKC β on the autophagy was also investigated. Our results indicated that cisplatin promoted PKC β in Hela cells. The PKC β inhibitor reduced the cisplatin-induced apoptosis, whereas increased the cisplatin-induced autophagy in Hela cells. On the other side, the PKC β overexpression aggravated the cisplatin-induced apoptosis, whereas down-regulated the cisplatin-induced autophagy. Taken together, our study firstly recognized the involvement of PKC β in the cytotoxicity of cisplatin via inhibiting autophagy in cervical cancer cells. We propose that PKC β would sensitize cervical cancer cells to chemotherapy via reducing the chemotherapy induced autophagy in cancer cells.

The eukaryotic translation initiation factor 3a (eIF3a) is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. Our previous study identified that it was correlated with platinum response in lung cancer. The current study aims to test the hypothesis that eIF3a may affect the drug response and prognosis of ovarian cancer patients receiving platinum-based chemotherapy by regulating xeroderma pigmentosum complementation group C (XPC) and p27(Kip1). Immunohistochemistry and western blot was used to determine the expression of eIF3a in 126 human ovarian cancer tissues followed by association analysis of eIF3a expression with patient's response and survival. Ectopic over-expression and RNA interference knockdown of eIF3a were carried out in A2780/cisplatin (DDP) and its parental A2780 cells, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin by employing MTT assay. Western Blot analyses were also carried out to determine the regulation of eIF3a on XPC and p27(Kip1). eIF3a expression was associated with response of ovarian cancer patients to DDP-based chemotherapy and their survival. Overexpression and knockdown of eIF3a increased and decreased the cellular response to cisplatin in A2780/DDP and A2780 cells, respectively. In addition, XPC and p27(Kip1) were down regulated by eIF3a. eIF3a improves ovarian cancer patients' response to DDP-based chemotherapy via down regulating XPC and p27(Kip1).

The treatment of renal cell carcinoma (RCC) with chemotherapy remains a challenge; therefore, improving the knowledge of the molecular mechanisms underlying RCC chemoresistance and developing novel therapeutic strategies is important. Dedicator of cytokinesis 1 (DOCK1), the first member of the DOCK family to be discovered, displays various roles during tumorigenesis; however, its role during RCC progression is not completely understood. Therefore, the present study aimed to clarify the function of DOCK1 and 1‑[2‑(3'‑(trifluoromethyl)‑(1,1'‑biphenyl)‑4‑yl)‑2‑oxoethyl]‑5‑pyrrolidinylsulfonyl‑2 (1H)‑pyridone (TBOPP), a DOCK1‑sensitive inhibitor, during RCC development and chemoresistance. The results of CCK‑8 and EdU assay indicated that TBOPP decreased RCC cell viability and proliferation compared with the control group, and sensitized RCC cells to cisplatin. Moreover, RCC cells with high DOCK1 expression levels displayed increased resistance to cisplatin, whereas DOCK1 knockdown enhanced the lethal effects of cisplatin on RCC cells. Furthermore, the results determined by western blotting, CCK‑8 and cell apoptosis assay indicated that TBOPP effectively reduced DOCK1 expression levels compared with the control group, and the TBOPP‑mediated cisplatin sensitizing effect was mediated by DOCK1 inhibition. The present study suggests that DOCK1 plays a vital role in RCC cell chemoresistance to cisplatin; therefore, TBOPP may serve as a novel therapeutic agent for RCC chemoresistance.

Poria cocos (Schw.) Wolf (Poria) is a well-known traditional medicinal fungus. It has been considered to possess spleen-invigorating (Jianpi) effects in traditional Chinese medicine, and is used clinically to treat spleen deficiency (Pixu) with symptoms of intestinal disorders such as diarrhea, indigestion, mucositis and weight loss.

The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1-/- mice. The nephrotoxicity was assessed in the wild-type and Mate1-/- mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1-/- mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients.

Drug resistance limits the treatment effect of cisplatin-based chemotherapy in head and neck squamous cell carcinoma (HNSCC), and the underlying mechanism is not fully understood. The aim of this study was to explore the cause of cisplatin resistance in HNSCC.

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.

Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy.

To reveal roles of reactive oxygen species (ROS) status in chemotherapy resistance and to develop a ROS scoring system for prognosis prediction in ovarian cancer.

Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-κB-mediated inflammatory effects. Up-regulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-κb is one of the key mechanisms leading to pyroptosis. This study aims to explore the effects of vitamin D/VDR on the pyroptosis pathway in cisplatin induced acute kidney injury (AKI) models. Our results showed that in wide type mice, renal function loss, tissue injury and cell death induced by cisplatin were alleviated by pretreatment of high-dose paricalcitol(a VDR agonist) accompanied with up-regulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1β (features of pyroptosis). While, in VDR knock out mice, cisplatin induced more severer renal injury and further increased pyroptosis related protein than the wild type mice and the effect of paricalcitol were also eliminated. In tubular cell specific VDR-over expressing mice, those renal injury index as well as pyroptosis phenotype were significantly reduced by low-dose paricalcitol pretreatment with upregulated VDR expression compared with WT mice. In vitro data using gain and lose function experiments in Human tubular epithelial cell (HK-2) were consistent with the observation as in vivo work. Our further experiments in both animal and cell culture work has found that the level of IκBα(Inhibitor of NF-κB) were decreased and the nuclear level of NF-κB p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse up-regulation of nuclear NF-κB p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-κB-mediated NLRP3/Caspase-1/GSDMD pyroptosis.

Cisplatin (CDDP) is extensively used for esophageal adenocarcinoma (EAC) chemotherapy, while cisplatin resistance is getting worse. microRNA-181a-5p (miR-181a-5p) has been reported to play an important role in various human cancers. However, the effect and underlying mechanism of miR-181a-5p in cisplatin resistance of EAC remain unclear.

Renal accumulation and exposure of cadmium originating from pollution in agricultural land and the prevalence of cigarette smoking remains an unneglectable human health concern. Whereas cadmium exposure has been correlated with increased incidence of a variety of kidney diseases, little is known pertaining to its effect on renal drug disposition and response in patients. Here, we report that cadmium exposure significantly increased the activity of organic cation transporter 2 (OCT2), a critical renal drug transporter recommended in United States Federal Drug Administration guidance for assessment during drug development. Cadmium enhanced OCT2 trafficking to the cell membrane both in vitro and in vivo. Mechanistically cadmium-mediated OCT2 translocation was found to involve protein-protein interaction between serine/threonine-protein kinase AKT2, calcium/calmodulin and the AKT substrate AS160 in in vitro cellular studies. The formed protein complex could selectively facilitate phosphorylation of AKT2 at T309, which induced translocation of OCT2 to the plasma membrane. Moreover, cadmium exposure markedly exacerbated nephrotoxicity induced by cisplatin, an OCT2 substrate, by increasing its accumulation in the mouse kidney. Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.

MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. In vivo evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.

Aurora-A overexpression is common in various types of cancers and has been shown to be involved in tumorigenesis through different signaling pathways, yet how the deregulation affects cancer therapeutics remains elusive. Here we showed that overexpression of Aurora-A rendered esophageal cancer cells resistance to cisplatin (CDDP) by inhibiting apoptosis. By using an apoptosis array, we identified a downstream gene, p21-activated kinase 7 (PAK7). PAK7 was upregulated by Aurora-A overexpression at both mRNA and protein levels. Importantly, the expression levels of Aurora-A and PAK7 were correlated in ESCC primary samples. Chromatin immunoprecipitation (ChIP) assay revealed that binding of E2F1 to the promoter of PAK7 was significantly enhanced upon Aurora-A activation, and knockdown of transcription factor E2F1 decreased PAK7 expression, suggesting that Aurora-A regulated PAK7 through E2F1. Furthermore, we demonstrated that PAK7 knockdown led to increased apoptosis, and Aurora-A-induced resistance to CDDP was reversed by downregulation of PAK7, suggesting PAK7 was a downstream player of Aurora-A that mediated chemoresistance of ESCC cells to CDDP. Our data suggest that PAK7 may serve as an attractive candidate for therapeutics in ESCC patients with Aurora-A abnormality.

Nephrotoxicity is a major adverse reaction of cisplatin-based chemotherapy. Organic cation transporter 2 (OCT2) which is located on the basement membrane of human proximal renal tubules is responsible for the renal accumulation of cisplatin and its nephrotoxicity. This study aimed to investigate the protective effect of PPIs to CP-induced nephrotoxicity. Three kinds of PPIs including lansoprazole, omeprazole and rabeprazole (Rab) were co-administrated with CP to mice. In addition, OCT2-overexpressed HEK293, HK-2 and A549 cells were co-incubated with CP and PPIs. The results showed that PPIs can attenuate CP-induced increase of CRE, BUN and histological damage of kidney. Among the three PPIs, Rab was found with a superior protective effect. It significantly reduced the accumulation of CP in OCT2-overexpressed HEK293 cells and in the renal cortex tissues of mice, but not in HK-2 cells. Moreover, Rab reduced the expression levels of cleaved-caspase-3, RIPK1, RIPK3, MLKL and p-MLKL and the apoptosis rate of renal tubular cells induced by CP in vivo, but not in HK-2 cells. However, Rab increased the viability of CP-treated cells in a concentration-dependent manner and attenuated CP-induced apoptosis and necroptosis in OCT2 over-expressed HEK293 cells. Finally, we demonstrated that Rab have no influence on the antitumor effect of CP. In conclusion, Rab attenuate CP-induced nephrotoxicity mainly through inhibiting OCT2-mediated CP uptake, without interfering with its anti-tumor property of inducing apoptosis and necroptosis.

Our previous study found that Qiong-Yu-Gao (QYG), a traditional Chinese medicine formula derived from Rehmanniae Radix, Poria, and Ginseng Radix, has protective effects against cisplatin-induced acute kidney injury (AKI), but the underlying mechanisms remain unknown. In the present study, the potential role of gut microbiota in the nephroprotective effects of QYG was investigated. We found that QYG treatment significantly attenuated cisplatin-induced AKI and gut dysbiosis, altered the levels of bacterial metabolites, with short-chain fatty acids (SCFAs) such as acetic acid and butyric acid increasing and uremic toxins such as indoxyl sulfate and p-cresyl sulfate reducing, and suppressed histone deacetylase expression and activity. Spearman's correlation analysis found that QYG-enriched fecal bacterial genera Akkermansia, Faecalibaculum, Bifidobacterium, and Lachnospiraceae_NK4A136_group were correlated with the altered metabolites, and these metabolites were also correlated with the biomarkers of AKI, as well as the indicators of fibrosis and inflammation. The essential role of gut microbiota was further verified by both the diminished protective effects with antibiotics-induced gut microbiota depletion and the transferable renal protection with fecal microbiota transplantation. All these results suggested that gut microbiota mediates the nephroprotective effects of QYG against cisplatin-induced AKI, potentially via increasing the production of SCFAs, thus suppressing histone deacetylase expression and activity, and reducing the accumulation of uremic toxins, thereby alleviating fibrosis, inflammation, and apoptosis in renal tissue. IMPORTANCE Cisplatin-induced acute kidney injury is the main limiting factor restricting cisplatin's clinical application. Accumulating evidence indicated the important role of gut microbiota in pathogenesis of acute kidney injury. In the present study, we have demonstrated that gut microbiota mediates the protective effects of traditional Chinese medicine formula Qiong-Yu-Gao against cisplatin-induced acute kidney injury. The outputs of this study would provide scientific basis for future clinical applications of QYG as prebiotics to treat cisplatin-induced acute kidney injury, and gut microbiota may be a promising therapeutic target for chemotherapy-induced nephrotoxicity.