Selection and characterization of a human ovarian cancer cell line resistant to auranofin

// Ida Landini 1 , Andrea Lapucci 1 , Alessandro Pratesi 2 , Lara Massai 2 , Cristina Napoli 3 , Gabriele Perrone 1 , Pamela Pinzani 4 , Luigi Messori 2, * , Enrico Mini 1, * and Stefania Nobili 3, * 1 Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy 2 Department of Chemistry “Ugo Schiff”, University of Florence, Firenze, Italy 3 Department of Health Sciences, University of Florence, Firenze, Italy 4 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy * These authors have contributed equally to this work Correspondence to: Enrico Mini, email: enrico.mini@unifi.it Stefania Nobili, email: stefania.nobili@unifi.it Luigi Messori, email: luigi.messori@unifi.it Keywords: auranofin; tumour drug resistance; human tumour cell lines; drug effects; gene expression Received: March 24, 2017 Accepted: August 08, 2017 Published: October 09, 2017 ABSTRACT The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofin-sensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of gold accumulation occurred in auranofin-resistant A2780 cells. Also, moderately higher thioredoxin reductase activity in A2780/AF-R cells was observed while no changes in intracellular glutathione content occurred. Resistance to auranofin was associated with a low level of cross-resistance to some investigational gold compounds as well as to oxaliplatin and other anticancer drugs with different mode of action (i.e. melphalan, vinblastine, doxorubicin, etoposide, and paclitaxel). Reduced gold accumulation was associated to substantial gene expression changes in various influx (e.g. SLC22A1, SLC47A1, SLCO1B1 ) and efflux (e.g. ABCB1, ABCC2, ABCC3 ) transporters. The expression levels of selected proteins (i.e. SLC22A1, SLC47A1, P-gp) were also changed accordingly. These data provide evidence that multiple drug transporters may act as mediators of transport of auranofin and other gold compounds in cancer cells. Further investigation into the molecular mechanisms mediating transport of auranofin and new gold complexes in view of their potential clinical application in the treatment of cancer is warranted.