Unexpected Enhancement of Cytotoxicity of Cisplatin in a Rat Kidney Proximal Tubular Cell Line Overexpressing Mitochondrial Glutathione Transport Activity.

Lawrence H Lash

doi:10.3390/ijms23041993

Lawrence H Lash

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https://doi.org/10.3390/ijms23041993

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In previous studies, we identified the two principal transporters that mediate the uptake of glutathione (GSH) from cytoplasm into the mitochondrial matrix of rat kidney proximal tubular cells. We hypothesized that genetic modulation of transporter expression could markedly alter susceptibility of renal proximal tubular cells to a broad array of oxidants and mitochondrial toxicants. Indeed, we previously showed that overexpression of either of these transporters resulted in diminished susceptibility to several chemicals. In the present work, we investigated the influence of overexpression of the mitochondrial 2-oxoglutarate carrier (OGC) in NRK-52E cells on the cytotoxicity of the antineoplastic drug cisplatin. In contrast to previous results showing that overexpression of the mitochondrial OGC provided substantial protection of NRK-52E cells from injury due to several toxicants, we found a remarkable enhancement of cellular injury from exposure to cisplatin as compared to wild-type NRK-52E cells. Despite the oxidative stress that cisplatin is known to cause in the renal proximal tubule, the increased concentrations of mitochondrial GSH associated with OGC overexpression likely resulted in increased delivery of cisplatin to molecular targets and increased cellular injury rather than the typical protection observed in the previous work.

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Cisplatin ( known as cis-diamminedichloroplatinum (II) or CDDP) is a widely used anticancer drug that was approved for use in treating several cancers by the U.S Food and Drug Administration in 1978
To attempt to address the role of GSH and renal mitochondria in the disposition and mechanism of action of CDDP in renal proximal tubular cells, we investigated the impact of altered mitochondrial GSH status on CDDP-induced cytotoxicity
The total amount of cell death as indicated by lactate dehydrogenase (LDH) release and apoptosis in Normal Rat Kidney-52 Epithelial (NRK-52E)-oxoglutarate carrier (OGC) cells incubated with 50 or 100 μM CDDP are >100%, suggesting that a proportion of the cells detected by propidium iodide staining and flow cytometry and designated as sub-G1 are likely necrotic

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Cisplatin ( known as cis-diamminedichloroplatinum (II) or CDDP) is a widely used anticancer drug that was approved for use in treating several cancers by the U.S Food and Drug Administration in 1978. Several factors and cellular mechanisms have been identified as critical determinants of CDDP-induced nephrotoxicity These have included active uptake by proximal tubular cells by the organic cation transporter 2 (OCT2; Slc22a2) and the copper transporter 1 (CTR1; Slc31a1) [10,11], generation of oxidants and production of a cellular state of oxidative stress [12–24], endoplasmic reticulum stress [25,26], inflammation [27,28], various processes in mitochondria that can lead to energetic failure [28–40], and cell death involving autophagy and other pathways [34,41–46]. This list of cellular processes and functions that are adversely impacted by CDDP exposure does not, explain the molecular mechanism by which CDDP causes renal cellular injury. One of the intracellular targets for this hydrated, electrophilic form of CDDP appears to be glutathione (GSH), as conjugation of CDDP with GSH has been reported in rodent kidney studies [47–49]

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