Article

Projet
Protéines ABC, membranes et passage membranaire  
Ahcène BOUMENDJELMarine PEUCHMAUR,   
Titre
Ovarian cancer cells cisplatin sensitization agents selected by mass cytometry target ABCC2 inhibition  
Auteurs
E. Comsa, K.-A. Nguyen, F. Loghin, A. Boumendjel, M. Peuchmaur, T. Andrieu, P. Falson.
Edition
Future Med. Chem. 2018, under press
Année
2018
Résumé
Overcoming cisplatin resistance in ovarian cancer remains a spiny problem as tumors frequently develop resistance against drugs, a mechanism in which ATP-binding cassette (ABC) transporters received attention because of their role in drugs bioavailability and toxicity. Previous studies left the spotlight on ABCC2, an apical efflux pump highly expressed in intense metabolic organs and barriers, displaying an overexpression in certain cisplatin-resistant cancers. Our goal was to find compounds restricting their inhibition capacity to the cisplatin efflux mediated by the pump, without altering its important physiological and metabolic role. We evaluated a series of furanones we recently identified as inhibitors of ABCC2-mediated calcein efflux on cisplatin accumulation in resistant ovarian cancer cells. To quantify cisplatin accumulation, we set up an original method allowing direct quantitation of platinum (Pt) by employing cyTOF mass cytometry. We observed a wide range of efficacies of the series on cisplatin efflux inhibition but strikingly, not correlated with that of calcein, suggesting distinct efflux mechanisms mediated by ABCC2. Among these furanones derivatives, some led to a full Pt accumulation and efficiently re-sensitized cisplatin-resistant A2780 cells to cisplatin toxicity while preserving most of the calcein efflux activity. 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.