Membrane transporters as mediators of toxicities induced by chemotherapeutic agents

• Applicant: Professor Dr. Giuliano Ciarimboli
• Subject Area: Anatomy and Physiology ; Nephrology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 389197969

• Final Report Year: 2024

Final Report Abstract

One of the main renal functions is the elimination of solutes via both glomerular filtration and tubular secretion, which takes place principally via epithelial cells of the proximal tubules. Here specialized transporters extract solutes from the circulation and extrude them into the urine in a coordinated process. Thereby, uptake of the chemotherapeutic drug cisplatin (CDDP) via the basolaterally located human organic cation transporter 2 (hOCT2) mediates the development of specific toxicities to the proximal tubule self. On the other hand, expression of the Multidrug- and Toxin-Extrusion protein 1 (MATE1) in the urine-facing membrane of proximal tubules cells is negatively associated with CDDP nephrotoxicity. The OCT2 is present also in other cells such as cells of the dorsal root ganglia and of the cochlea and may be co-responsible for CDDP peripheral neurotoxicity and ototoxicity. CDDP is a potent cytostatic drug which is curative against testicular cancer but whose use is limited by its severe acute and chronic unwanted toxicities. In this project the molecular mechanisms of CDDP toxicities and their dependence on transporters were investigated by performing proteomic, phosphoproteomic, and degradomic analysis of the kidneys from wild type (WT) mice and mice with genetic deletion of OCT2 after acute or chronic treatment with CDDP. Moreover, it has been investigated whether OCT2 and MATE1 are suitable targets of protective interventions aimed at reducing undesired side effects of chemotherapy with CDDP in kidney, cochlea and neuronal cells. Specifically, we have examined whether inhibition or regulation of these transporters is able to decrease CDDP toxicities in vitro, and whether autophagy activation can protect cells against toxicities from platinum derivatives.

Publications

• Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations. Frontiers in Chemistry, 6.
  Hucke, Anna; Park, Ga Young; Bauer, Oliver B.; Beyer, Georg; Köppen, Christina; Zeeh, Dorothea; Wehe, Christoph A.; Sperling, Michael; Schröter, Rita; Kantauskaitè, Marta; Hagos, Yohannes; Karst, Uwe; Lippard, Stephen J. & Ciarimboli, Giuliano
  
• Single-nephron proteomes connect morphology and function in proteinuric kidney disease. Kidney International, 93(6), 1308-1319.
  Höhne, Martin; Frese, Christian K.; Grahammer, Florian; Dafinger, Claudia; Ciarimboli, Giuliano; Butt, Linus; Binz, Julia; Hackl, Matthias J.; Rahmatollahi, Mahdieh; Kann, Martin; Schneider, Simon; Altintas, Mehmet M.; Schermer, Bernhard; Reinheckel, Thomas; Göbel, Heike; Reiser, Jochen; Huber, Tobias B.; Kramann, Rafael; Seeger-Nukpezah, Tamina; ... & Rinschen, Markus M.
  
• An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection. Archives of Toxicology, 93(10), 2835-2848.
  Hucke, Anna; Rinschen, Markus M.; Bauer, Oliver B.; Sperling, Michael; Karst, Uwe; Köppen, Christina; Sommer, Karolin; Schröter, Rita; Ceresa, Cecilia; Chiorazzi, Alessia; Canta, Annalisa; Semperboni, Sara; Marmiroli, Paola; Cavaletti, Guido; Schlatt, Stefan; Schlatter, Eberhard; Pavenstädt, Hermann; Heitplatz, Barbara; Van Marck, Veerle; ... & Ciarimboli, Giuliano
  
• Effects of Single Nucleotide Polymorphism Ala270Ser (rs316019) on the Function and Regulation of hOCT2. Biomolecules, 9(10), 578.
  Frenzel, Dominik; Köppen, Christina; Bolle, Bauer Oliver; Karst, Uwe; Schröter, Rita; Tzvetkov, Mladen V. & Ciarimboli, Giuliano
  
• Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2. SLAS Discovery, 24(9), 904-914.
  Snieder, Beatrice; Brast, Sabine; Grabner, Alexander; Buchholz, Sven; Schröter, Rita; Spoden, Gilles A.; Florin, Luise; Salomon, Johanna; Albrecht, Tobias; Barz, Vivien; Sparreboom, Alex & Ciarimboli, Giuliano
  
• Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys. International Journal of Molecular Sciences, 20(21), 5303.
  Oswald, Stefan; Müller, Janett; Neugebauer, Ute; Schröter, Rita; Herrmann, Edwin; Pavenstädt, Hermann & Ciarimboli, Giuliano
  
• The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury. Kidney International, 95(2), 333-349.
  Späth, Martin R.; Bartram, Malte P.; Palacio-Escat, Nicolàs; Hoyer, K. Johanna R.; Debes, Cedric; Demir, Fatih; Schroeter, Christina B.; Mandel, Amrei M.; Grundmann, Franziska; Ciarimboli, Giuliano; Beyer, Andreas; Kizhakkedathu, Jayachandran N.; Brodesser, Susanne; Göbel, Heike; Becker, Jan U.; Benzing, Thomas; Schermer, Bernhard; Höhne, Martin; Burst, Volker; ... & Rinschen, Markus M.
  
• Cetirizine Reduces Gabapentin Plasma Concentrations and Effect: Role of Renal Drug Transporters for Organic Cations. The Journal of Clinical Pharmacology, 60(8), 1076-1086.
  Costa, Ana Carolina Conchon; Yamamoto, Priscila Akemi; Lauretti, Gabriela Rocha; de Lima Benzi, Jhohann Richard; Zanelli, Cleslei Fernando; Barz, Vivien; Ciarimboli, Giuliano & de Moraes, Natália Valadares
  
• Fast simultaneous quantification of gabapentin and cetirizine in cell lysates by means of HPLC-MS/MS. Journal of Pharmaceutical and Biomedical Analysis, 184, 113172.
  Schlatt, Lukas; Costa, Ana Carolina Conchon; Barz, Vivien; Ciarimboli, Giuliano & Karst, Uwe
  
• Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K. International Journal of Molecular Sciences, 21(14), 5157.
  Kantauskaitė, Marta; Hucke, Anna; Reike, Moritz; Ahmed, Eltayeb Sara; Xiao, Chuyan; Barz, Vivien & Ciarimboli, Giuliano
  
• Expression and Function of Organic Cation Transporter 2 in Pancreas. Frontiers in Cell and Developmental Biology, 9.
  Schorn, Sandra; Dicke, Ann-Kristin; Neugebauer, Ute; Schröter, Rita; Friedrich, Maren; Reuter, Stefan & Ciarimboli, Giuliano
  
• Properties of Transport Mediated by the Human Organic Cation Transporter 2 Studied in a Polarized Three-Dimensional Epithelial Cell Culture Model. International Journal of Molecular Sciences, 22(17), 9658.
  Koepp, Tim N.; Tokaj, Alexander; Nedvetsky, Pavel I.; Conchon, Costa Ana Carolina; Snieder, Beatrice; Schröter, Rita & Ciarimboli, Giuliano
  
• Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1. Frontiers in Pharmacology, 11.
  Ciarimboli, Giuliano
  
• Exacerbation of Cisplatin Cellular Toxicity by Regulation of the Human Organic Cation Transporter 2 through Angiotensin II. International Journal of Molecular Sciences, 23(24), 15866.
  Kantauskaite, Marta; Hucke, Anna; Snieder, Beatrice & Ciarimboli, Giuliano
  
• Interaction of Masitinib with Organic Cation Transporters. International Journal of Molecular Sciences, 23(22), 14189.
  Harrach, Saliha; Haag, Jasmin; Steinbüchel, Martin; Schröter, Rita; Neugebauer, Ute; Bertrand, Jessica & Ciarimboli, Giuliano
  
• Role of Organic Cation Transporter 2 in Autophagy Induced by Platinum Derivatives. International Journal of Molecular Sciences, 23(3), 1090.
  Eltayeb, Sara Ahmed; Ciarimboli, Giuliano; Beul, Katrin; Seno, Di Marco Giovana & Barz, Vivien
  
• Regulation of Transporters for Organic Cations by High Glucose. International Journal of Molecular Sciences, 24(18), 14051.
  Steinbüchel, Martin; Menne, Johannes; Schröter, Rita; Neugebauer, Ute; Schlatter, Eberhard & Ciarimboli, Giuliano
  
• Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin. International Journal of Molecular Sciences, 24(14), 11486.
  Hucke, Anna; Schröter, Rita; Ceresa, Cecilia; Chiorazzi, Alessia; Canta, Annalisa; Semperboni, Sara; Marmiroli, Paola; Cavaletti, Guido; Gess, Burkhard & Ciarimboli, Giuliano