Research Article For reprint orders, please contact: reprints@future-science.com Ovarian cancer cells cisplatin sensitization agents selected by mass cytometry target ABCC2 inhibition Elisabeta Comsa 1,2 , Kim-Anh Nguyen 3,4 , Felicia Loghin 2 , Ahc` ene Boumendjel 3,4 , Marine Peuchmaur 3,4 , Thibault Andrieu 5 & Pierre Falson* ,1 1 Drug Resistance & Membrane Proteins Laboratory, Molecular Microbiology & Structural Biochemistry, UMR 5086 CNRS/Universit ´ e Lyon 1, Institut de Biologie et Chimie des Prot´ eines, Lyon, France 2 Toxicology Department, Faculty of Pharmacy, University of Medicine & Pharmacy ‘Iuliu Hatieganu,’ Cluj-Napoca, Romania 3 D´ epartement de Pharmacochimie Mol ´ eculaire DPM, Univ. Grenoble Alpes, UMR 5063, 38041 Grenoble, France 4 CNRS, DPM UMR 5063, 38041 Grenoble, France 5 SFR Biosciences, Tour 1, UMS 3444 Lyon, France *Author for correspondence: pierre.falson@ibcp.fr Aim: Cisplatin resistance in ovarian cancer remains a complex problem as tumors frequently develop re- sistance against drugs, a mechanism sometimes mediated by ATP-Binding Cassette transporters. Our goal was to fnd compounds restricting their inhibition capacity to the cisplatin effux mediated by ABCC2 pump, among previously identifed inhibitors, derived from the 2- indolylmethylenebenzofuranones. Results/methodology: An original method setup allows direct quantitation of platinum by employing cyTOF mass cytometry. Among tested derivatives, some led to a full platinum accumulation and effciently resensitized cisplatin-resistant A2780 cells to cisplatin while preserving most of the calcein effux activity. Conclusion: CyTOF is therefore a powerful and promising method to quantify cisplatin accumulation that may be used in the clinical setting to improve and personalize cancer treatment. First draft submitted: 6 December 2017; Accepted for publication: 14 March 2018; Published online: 31 May 2018 Keywords: ABCC2 aurones • cisplatin resistance • cyTOF inhibitors • mass cytometry • multidrug resistance • ovarian cancer Various types of cancers, including sarcomas, some carcinomas (e.g., small-cell lung cancer and ovarian cancer), lymphomas and germ cell tumors are treated with cisplatin, cisplatinum or cis-diamminedichloroplatinum (II). Cisplatin, cisplatinum or cis-diamminedichloroplatinum (II) is a platinum (Pt) based chemotherapy drug, the first member of its class, including also carboplatin and oxaliplatin. After undergoing hydrolysis in the cytoplasm, it reverts with DNA to produce both intra- and interstrands cross-links. These cross-links impair DNA replication and transcription [1,2]. Unfortunately, despite an initial response, tumors frequently overcome the drug effect, ultimately leading to a highly resistant form. To tackle the resistance problem, several cisplatin analogs were designed and developed, but unfortunately this proved to be a challenging goal [1]. Clinical studies indicated at least a twofold resistance, primarily since expected therapy responses were observed only after a dosage doubling of cisplatin in drug-intensive therapy protocols. Resistance to cisplatin may be substantially greater as shown by clinical studies conducted on tumor cell lines established from refractory tumors, that require cytotoxic concentrations as much as 50- to 100-fold more than those needed for sensitive tumor cells [3,4]. Several mechanisms contribute to resistance toward cisplatin, such as reduced uptake or increased efflux of Pt compounds via heavy metal transporters, cellular compartmentation, detoxification of bioactive Pt aquo-complexes by sulfur-rich containing peptides or proteins, increased DNA repair and alterations in apoptotic signaling pathways [5]. Resistance to cisplatin can be intrinsic (e.g., colon carcinomas) or acquired (e.g., ovarian carcinomas), and some tumor specimens show no tendency to acquire resistance (e.g., testicular cancer) [6]. Reductions of intracellular cisplatin levels in the range of 20–70% have been reported in a variety of cell lines [1,7]. Future Med. Chem. (Epub ahead of print) ISSN 1756-8919 10.4155/fmc-2017-0308 C  2018 Newlands Press