Tariquidar and paclitaxel therapy in ovarian cancer

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 (OvCa). However, in clinical trials, co-administration of P-gp inhibitors and anti-cancer drugs has not resulted in the efficient reversal of drug resistance. To improve administration, we encapsulated the 3rd 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 OvCa cell line pairs. Analyzing publicly available datasets, we found that overexpression of P-gp in OvCa 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, while 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% versus 16.9%, p=0.0007) and number of metastases (44.4% versus 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 OvCa cells to paclitaxel. LP(XR,PCT) should be considered for clinical testing in patients with P-gp-overexpressing tumors.

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