Abstract
Cancer treatment with platinum compounds is an important achievement of modern chemotherapy. However, despite the beneficial effects, the clinical impact of these agents is hampered by the development of drug resistance as well as dose-limiting side effects. The efficacy but also side effects of platinum complexes can be mediated by uptake through plasma membrane transporters. In the kidneys, plasma membrane transporters are involved in their secretion into the urine. Renal secretion is accomplished by uptake from the blood into the proximal tubules cells, followed by excretion into the urine. The uptake process is mediated mainly by organic cation transporters (OCT), which are expressed in the basolateral domain of the plasma membrane facing the blood. The excretion of platinum into the urine is mediated by exchange with protons via multidrug and toxin extrusion proteins (MATE) expressed in the apical domain of plasma membrane. Recently, the monofunctional, cationic platinum agent phenanthriplatin, which is able to escape common cellular resistance mechanisms, has been synthesized and investigated. In the present study, the interaction of phenanthriplatin with transporters for organic cations has been evaluated. Phenanthriplatin is a high affinity substrate for OCT2, but has a lower apparent affinity for MATEs. The presence of these transporters increased cytotoxicity of phenanthriplatin. Therefore, phenanthriplatin may be especially effective in the treatment of cancers that express OCTs, such as colon cancer cells. However, the interaction of phenanthriplatin with OCTs suggests that its use as chemotherapeutic agent may be complicated by OCT-mediated toxicity. Unlike cisplatin, phenanthriplatin interacts with high specificity with hMATE1 and hMATE2K in addition to hOCT2. This interaction may facilitate its efflux from the cells and thereby decrease overall efficacy and/or toxicity.
Highlights
Cancer is an important cause of death worldwide (Chakraborty et al, 2018)
Transporters for organic cations, when expressed in polarized cells such as hepatocytes and renal proximal tubules cells, mediate the vectorial movement of substances through cells, which under physiological conditions results in the secretion of organic cations into the bile and urine, respectively. hOCT1 and hOCT2 are expressed in the basolateral membrane of hepatocytes and renal proximal tubule cells, respectively, whereas hMATEs are localized on the apical domain of these cells
We show that phenanthriplatin interacts with transporters for organic cations and that it is even more effective against tumor cells expressing hOCT2
Summary
Cancer is an important cause of death worldwide (Chakraborty et al, 2018). At present, three major therapeutic strategies to treat cancer are used, namely, surgery, radiotherapy, and chemotherapy (Chakraborty et al, 2018). The currently approved FDA platinum anticancer agents cisplatin, oxaliplatin, and carboplatin have proved efficacious against a wide variety of tumors, with cisplatin treatment considered to be curative for testicular cancer (Einhorn, 2002; Chovanec et al, 2016). Despite their beneficial effects, treatment with these agents is hampered by the development of drug resistance as well as dose-limiting side effects (Rabik and Dolan, 2007; Kuok et al, 2017). Monofunctional agents disobey the classical structure-activity relationships (SARs), which stipulate that active platinum complexes should have two labile leaving groups to form bifunctional adducts with DNA targets in the nucleus (Sherman and Lippard, 1987)
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