An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection

Hucke, Anna; Rinschen, Markus M.; Bauer, Oliver; Sperling, Michael; Kärst, Uwe; Köppen, Christina; Sommer, Karolin; Schröter, Rita; Ceresa, C; Chiorazzi, A; Canta, A; Semperboni, Sara; Marmiroli, P; Cavaletti, Guido; Schlatt, Stefan; Schlatter, Eberhard; Pavenstädt, Hermann; Heitplatz, Barbara; Sparreboom, Alex; Barz, Vivien; Knief, Arne; Deuster, Dirk; Zehnhoff‐Dinnesen, Antoinette am; Ciarimboli, Giuliano

doi:10.1007/s00204-019-02557-9

Cited by 17 publications

(24 citation statements)

References 47 publications

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“…17,18 In rodent kidney, in addition to Oct2, Oct1 is also involved in the basal uptake of cisplatin into the tubular cells. 49 On the apical side, consistent findings have implicated a role by MATE transporters in the secretion of cisplatin into the urine. 19 Whereas the present study focuses on the primary renal transporter system OCT/ MATE for cisplatin transport, and thus the interaction between Cd and cisplatin in causing nephrotoxicity, it is likely that Cd exposure affects the activities of additional membrane transporters.…”

Section: Discussionmentioning

confidence: 72%

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Yang

Tang

Guo

et al. 2020

Kidney International

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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.

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Section: Discussionmentioning

confidence: 72%

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Yang

Tang

Guo

et al. 2020

Kidney International

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“…Yonezawa et al ( 2006 ) show that cisplatin and oxaliplatin are substrates for human OCTs, while carboplatin is not. Studies using OCT knockout mice in conjunction with a low dose cyclic cisplatin administration protocol suggest functional blocking of OCTs as a strategy to prevent cisplatin ototoxicity (Hucke et al 2019 ). It is unclear whether OCTs account for all uptake of platinum in the cochlea, if OCTs are present in all inner ear cell types, or if there are OCT-independent mechanisms of uptake that may contribute to ototoxicity.…”

Section: Discussionmentioning

confidence: 99%

Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents

Gersten

Fitzgerald

Fernandez

et al. 2020

JARO

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Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.

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“…This toxicity impairs the tubular functions and manifests as acute kidney injury (AKI), which can progress to chronic kidney disease. Up to around 20% of AKI-related deaths are associated with cisplatin-based chemotherapy [35,36]. Proximal tubule cells are able to accumulate cisplatin, as five-fold serum concentrations are found in these cells [37].…”

Section: Discussionmentioning

confidence: 99%

Effects of Single Nucleotide Polymorphism Ala270Ser (rs316019) on the Function and Regulation of hOCT2

et al. 2019

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The human organic cation transporter 2 (hOCT2) is highly expressed in proximal tubules of the kidneys, where it plays an important role in the secretion of organic cations. Since many drugs are organic cations, hOCT2 has relevant pharmacological implications. The hOCT2 gene is polymorphic, and the nonsynonymous single nucleotide polymorphism (SNP) causing the substitution of alanine at position 270 of the protein sequence with serine (Ala270Ser) is present with high frequency in the human population. Therefore, Ala270Ser has potentially important pharmacologic consequences. Here, we analyzed the transport properties and rapid regulation of hOCT2 wildtype and hOCT2 Ala270Ser expressed in human embryonic kidney cells using real-time uptake measurements. Moreover, we compared the expression of hOCT2 in the plasma membrane determined by biotinylation experiments and the cellular transport and toxicity of cisplatin measured by inductively coupled plasma mass spectrometry and a viability test, respectively. The transport characteristics and regulation of the wildtype and mutated hOCT2 were very similar. Interestingly, a higher affinity of hOCT2 Ala270Ser for creatinine was observed. Compared with hOCT2 wildtype, the plasma membrane expression, cisplatin transport, and cisplatin-associated toxicity of hOCT2 Ala270Ser were significantly lower. In conclusion, these findings suggest that Ala270Ser has subtle but important effects on hOCT2 function, which are probably difficult to detect in studies with patients.

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An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection

Cited by 17 publications

References 47 publications

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents

Effects of Single Nucleotide Polymorphism Ala270Ser (rs316019) on the Function and Regulation of hOCT2

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