title: Modulating cancer multidrug resistance by sertraline in combination with a nanomedicine.
abstract: Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacle in cancer treatment. The ATP Binding Cassettes (ABC) transporter super family that act as extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins have prominent roles in cancer MDR. One of the most efficient strategies to modulate this active drug efflux from the cells is to physically block the pump proteins and thus change the balance between drug influx and efflux toward an accumulation of drug inside the cell, which eventually cumulates into cell death. MDR modulators (also known as chemosensitizers) were found among drugs approved for non-cancer indications. Yet, toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Previous reports have shown that drugs belonging to the selective serotonin reuptake inhibitors (SSRI) family, which are clinically used as antidepressants, can act as effective chemosensitizers both in vitro and in vivo in tumor bearing mouse models. Here, we set out to explore whether sertraline (Zoloft®), a molecule belonging to the SSRI family, can be used as an MDR modulator. Combining sertraline with another FDA approved drug, Doxil® (pegylated liposomal doxorubicin), is expected to enhance the effect of chemotherapy while potentially reducing adverse effects. Our findings reveal that sertraline acts as a pump modulator in cellular models of MDR. In addition, in an aggressive and highly resistant human ovarian xenograft mouse model the use of sertraline in combination with Doxil® generated substantial reduction in tumor progression, with extension of the median survival of tumor-bearing mice. Taken together, our results show that sertraline could act as a clinically relevant cancer MDR inhibitor. Moreover, combining two FDA approved drugs, DOXIL®, which favor the influx of chemotherapy inside the malignant cell with sertraline, which blocks the extrusion pumps, could readily be available for clinical translation in the battle against resistant tumors.
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Department of Materials Sciences and Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Velthe
authors.initials: V
authors.lastname: Drinberg
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Department of Materials Sciences and Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Bitcover
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Department of Materials Sciences and Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Wolf
authors.initials: W
authors.lastname: Rajchenbach
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Department of Materials Sciences and Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: peer@tauex.tau.ac.il.
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D050997:Nanomedicine / Q000379:methods; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D020280:Sertraline / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D020280:Sertraline
keywords: Cancer MDR; Nanomedicine; SSRI; Sertraline