title: Reversal of Chemoresistance in Ovarian Cancer by Co-Delivery of a P-Glycoprotein Inhibitor and Paclitaxel in a Liposomal Platform.
abstract: The overexpression of permeability-glycoprotein (P-gp), an ABC transporter involved in the cellular exclusion of chemotherapeutic drugs, is a major factor in paclitaxel-resistant ovarian cancer. However, in clinical trials, co-administration of P-gp inhibitors and anticancer drugs has not resulted in the efficient reversal of drug resistance. To improve administration, we encapsulated the third-generation P-gp inhibitor tariquidar (XR-9576, XR), alone or in combination with paclitaxel (PCT) in liposomes (LP). After optimization, the liposomes demonstrated favorable physicochemical properties and the ability to reverse chemoresistance in experiments using chemosensitive/chemoresistant ovarian cancer cell line pairs. Analyzing publicly available datasets, we found that overexpression of P-gp in ovarian cancer is associated with a shorter progression-free and overall survival. In vitro, LP(XR) significantly increased the cellular retention of rhodamine 123, a P-gp substrate. LP(XR,PCT) synergistically inhibited cell viability, blocked proliferation, and caused G2-M arrest in paclitaxel-resistant SKOV3-TR and HeyA8-MDR cell lines overexpressing P-gp. Holographic imaging cytometry revealed that LP(XR,PCT) treatment of SKOV3-TR cells induced almost complete mitotic arrest, whereas laser scanning cytometry showed that the treatment induced apoptosis. In proof-of-concept preclinical studies, LP(XR,PCT), when compared with LP(PCT), significantly reduced tumor weight (43.2% vs. 16.9%, P = 0.0007) and number of metastases (44.4% vs. 2.8%, P = 0.012) in mice bearing orthotopic HeyA8-MDR ovarian tumors. In the xenografts, LP(XR,PCT) efficiently induced apoptosis and impaired proliferation. Our findings suggest that co-delivery of a P-gp inhibitor and paclitaxel using a liposomal platform can sensitize paclitaxel-resistant ovarian cancer cells to paclitaxel. LP(XR,PCT) should be considered for clinical testing in patients with P-gp-overexpressing tumors. Mol Cancer Ther; 15(10); 2282-93. ©2016 AACR.
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors.forename: Shravan Kumar
authors.initials: SK
authors.lastname: Sriraman
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Kenny
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors.forename: Ed
authors.initials: E
authors.lastname: Luther
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Torchilin
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, Illinois. elengyel@uchicago.edu.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008081:Liposomes; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage*; D011379:Prognosis
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D008081:Liposomes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; C421109:multidrug resistance-associated protein 1