Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury

Huang, Di; Wang, Chuangyuan; Duan, Yingjie; Meng, Qiang; Liu, Zhihao; Huo, Xiaokui; Sun, Huijun; Ma, Xiaodong; Liu, Kexin

doi:10.1016/j.taap.2017.04.013

Cited by 46 publications

(31 citation statements)

References 37 publications

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“…We can only speculate on how this is regulated, but this could involve the Nrf2 pathway, as Nrf2-null mice developed more extensive nephrotoxicity after cisplatin treatment compared with wild types (Aleksunes et al, 2010). Nrf2-mediated signaling reduces expression of OCT2 in rat cortical tissue and Madin-Darby canine kidney cells, and increases expression of MATE1 in primary human proximal tubule cells, reducing renal cisplatin accumulation and toxicity (Shu et al, 2001;Atilano-Roque et al, 2016;Huang et al, 2017). In ciPTEC-parent, the involvement of Nrf2 in downregulation of OCT2 and upregulation of MATE1 could be confirmed, supporting previous in vivo and in vitro studies (Aleksunes et al, 2010;Atilano-Roque et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

et al. 2018

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Cisplatin is a cytostatic drug used for treatment of solid organ tumors. The main adverse effect is organic cation transporter 2 (OCT2)-mediated nephrotoxicity, observed in 30% of patients. The contribution of other renal drug transporters is elusive. Here, cisplatin-induced toxicity was evaluated in human-derived conditionally immortalized proximal tubule epithelial cells (ciPTEC) expressing renal drug transporters, including OCT2 and organic anion transporters 1 (OAT1) or 3 (OAT3). Parent ciPTEC demonstrated OCT2-dependent cisplatin toxicity (TC 50 34 6 1 mM after 24-hour exposure), as determined by cell viability. Overexpression of OAT1 and OAT3 resulted in reduced sensitivity to cisplatin (TC 50 45 6 6 and 64 6 11 mM after 24-hour exposure, respectively). This effect was independent of OAT-mediated transport, as the OAT substrates probenecid and diclofenac did not influence cytotoxicity. Decreased cisplatin sensitivity in OAT-expressing cells was associated directly with a trend toward reduced intracellular cisplatin accumulation, explained by reduced OCT2 gene expression and activity. This was evaluated by V max of the OCT2-model substrate ASP + (23.5 6 0.1, 13.1 6 0.3, and 21.6 6 0.6 minutes 21 in ciPTEC-parent, ciPTEC-OAT1, and ciPTEC-OAT3, respectively). Although gene expression of cisplatin efflux transporter multidrug and toxin extrusion 1 (MATE1) was 16.2 6 0.3-fold upregulated in ciPTEC-OAT1 and 6.1 6 0.7-fold in ciPTEC-OAT3, toxicity was unaffected by the MATE substrate pyrimethamine, suggesting that MATE1 does not play a role in the current experimental set-up. In conclusion, OAT expression results in reduced cisplatin sensitivity in renal proximal tubule cells, explained by reduced OCT2-mediated uptake capacity. In vitro drug-induced toxicity studies should consider models that express both OCT and OAT drug transporters.

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Section: Discussionmentioning

confidence: 99%

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

et al. 2018

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“…Besides, it was reported that p53 could widely regulate cisplatin‐induced renal injury and disease progression . The arrest, senescence and apoptosis of cells were induced by the activation of p53 .…”

Section: Discussionmentioning

confidence: 99%

“…The arrest, senescence and apoptosis of cells were induced by the activation of p53 . As a regulatory gene upstream of apoptotic protein, p53 was an important factor in regulating apoptosis and played an important role in the process of renal injury . In this study, p53 was significantly up regulated by cisplatin (Figure ) in the morbid condition.…”

Section: Discussionmentioning

confidence: 99%

“…The rats were randomly allocated into two groups ( n = 6): (1) Control group: physiological saline was injected intraperitoneally at the first day; (2) Cisplatin‐induced AKI group: cisplatin was injected intraperitoneally at a single dose of 12 mg/kg at the first day . Cisplatin was dissolved in physiological saline to confect the injection with the concentration of 20 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

“…During periods of AKI, glomerular filtration and renal excretion were reduced. To avoid this, it often demanded on adjusting the dose or dosing interval of drugs that were eliminated by kidney . AKI had a series of pathological processes, including massive death of endothelial cells and epithelial cells, obstruction of renal tubules, alteration of local microvascular blood flow and many immunological and inflammatory processes .…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Wang

Sun

Wang

et al. 2018

Journal of Pharmacy and Pharmacology

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The molecular mechanism of decreased expression of Oat1 and Oat3 was achieved through activating p53, and then increasing the expression of Bax and Caspase-3 and down regulating Bcl-2 in AKI rats. On this basis, the cumulative urinary excretion of cefdinir was significantly decreased and the plasma concentration of cefdinir was remarkably increased in AKI rats. However, the pharmacokinetic changes of cefditoren were not observed. Accordingly, cephalosporin antibiotics such as cefditoren should be firstly selected for the treatment in patients with AKI in clinic.

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Diphenhydramine increases the therapeutic window for platinum drugs by simultaneously sensitizing tumor cells and protecting normal cells

et al. 2020

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Platinum‐based compounds remain a well‐established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type‐specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug‐induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss. Formation and persistence of platination products in the DNA of individual nuclei were measured in drug‐exposed cell lines, in primary human tumor cells and in tissue sections using an immunocytochemical method. Using a mouse model of CP‐induced toxicity, the antihistaminic drug diphenhydramine (DIPH) and two methylated derivatives decreased DNA platination in normal tissues and also ameliorated nephrotoxicity, ototoxicity, and neurotoxicity. In addition, DIPH sensitized multiple cancer cell types, particularly ovarian cancer cells, to CP by increasing intracellular uptake, DNA platination, and/or apoptosis in cell lines and in patient‐derived primary tumor cells. Mechanistically, DIPH diminished transport capacity of CP efflux pumps MRP2, MRP3, and MRP5 particularly in its C2+C6 bimethylated form. Overall, we demonstrate that DIPH reduces side effects of platinum‐based chemotherapy and simultaneously inhibits key mechanisms of platinum resistance. We propose that measuring DNA platination after ex vivo exposure may predict the responsiveness of individual tumors to DIPH‐like modulators.

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Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury

Cited by 46 publications

References 37 publications

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Diphenhydramine increases the therapeutic window for platinum drugs by simultaneously sensitizing tumor cells and protecting normal cells

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