Endocytotic uptake of zoledronic acid by tubular cells may explain its renal effects in cancer patients receiving high doses of the compound

PloS One
Anja VerhulstPatrick C D'Haese

Abstract

Zoledronic acid, a highly potent nitrogen-containing bisphosphonate used for the treatment of pathological bone loss, is excreted unmetabolized via the kidney if not bound to the bone. In cancer patients receiving high doses of the compound renal excretion may be associated with acute tubular necrosis. The question of how zoledronic acid is internalized by renal tubular cells has not been answered until now. In the current work, using a primary human tubular cell culture system, the pathway of cellular uptake of zoledronic acid (fluorescently/radiolabeled) and its cytotoxicity were investigated. Previous studies in our laboratory have shown that this primary cell culture model consistently mimics the physiological characteristics of molecular uptake/transport of the epithelium in vivo. Zoledronic acid was found to be taken up by tubular cells via fluid-phase-endocytosis (from apical and basolateral side) as evidenced by its co-localization with dextran. Cellular uptake and the resulting intracellular level was twice as high from the apical side compared to the basolateral side. Furthermore, the intracellular zoledronic acid level was found to be dependent on the administered concentration and not saturable. Cytotoxic effects ho...Continue Reading

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Citations

Dec 10, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Cigir Biray AvciCumhur Gunduz
Apr 13, 2018·Drug and Chemical Toxicology·Ramakrishna Dasari, Sunil Misra
Mar 19, 2020·Toxins·Anika HimmelsbachClaudia Goettsch
Oct 8, 2016·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Christian SchemSanjay Tiwari

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Methods Mentioned

BETA
GTPases
confocal microscopy

Software Mentioned

Volocity
SPSS

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