Tariquidar

Tariquidar is a potent inhibitor of P-glycoprotein (Pgp), a 170-kDa transmembrane protein acting as a drug efflux pump to actively transport structurally unrelated compounds out of cells, that noncompetitively inhibits the basal the activity of ATPase associated with Pgp. Tariquidar contains a tertiary amine, dimethoxyphenyl group and amide group in its chemical structure, which contribute to its inhibition against Pgp. Results of in vitro assays of three different models have shown that Tariquidar inhibits Pgp with 50% inhibition concentration IC₅₀ values ranging from 15 to 223 nM. However, the inhibition by tariquidar is Pgp-specific and attenuated in tumor cell lines, where multidrug resistance is mediated by multidrug resistance-associated protein.

Reference

Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther. 2007 Apr;7(4):447-59.

Bankstahl JP, Bankstahl M, Römermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Müller M, Löscher W, Langer O, Kuntner C. Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study. Drug Metab Dispos. 2013 Apr;41(4):754-62. doi: 10.1124/dmd.112.049148. Epub 2013 Jan 10.

The reversal of multidrug resistance in ovarian carcinoma cells by co-application of tariquidar and paclitaxel in transferrin-targeted polymeric micelles.[Pubmed:27616277]

J Drug Target. 2017 Mar;25(3):225-234.

In this study, a transferrin (Tf)-modified polyethylene glycol-phosphatidyl ethanolamine (PEG-PE)-based micellar delivery system containing paclitaxel (PTX) and Tariquidar (TRQ), a potent third generation P-gp inhibitor, was prepared. The nanoformulation was evaluated by targeting efficiency, cellular association, cellular internalization pathway and cytotoxicity for reversal of PTX resistance on two multidrug resistant (MDR) ovarian carcinoma cell lines, SKOV-3TR and A2780-Adr. PTX and TRQ are both hydrophobic compounds. They were successfully encapsulated into the micellar structure containing vitamin E as the encapsulation enhancer. The Tf-targeted micelles were internalized mainly via clathrin-dependent endocytosis by both cell lines. For SKOV-3TR, additional mechanisms including caveolin-dependent endocytosis and macropinocytosis were found to play a significant role. The PTX cytotoxicity against the SKOV-3TR and A2780-Adr MDR cells was increased significantly in the presence of micellar encapsulation. However, unlike the A2780-Adr cell line, the Tf-targeting effect was significant on SKOV-3TR cells when co-administrated with TRQ. Penetration of the Tf-targeted micelles in a cancer cell spheroid culture was also investigated.

Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans.[Pubmed:27081167]

J Nucl Med. 2016 Aug;57(8):1265-8.

UNLABELLED: (11)C-elacridar and (11)C-Tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate-binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans. METHODS: Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either (11)C-elacridar or (11)C-Tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms. RESULTS: Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 +/- 0.06 muSv/MBq for (11)C-elacidar and 3.62 +/- 0.11 muSv/MBq for (11)C-Tariquidar. CONCLUSION: Our data indicate that both (11)C-elacridar and (11)C-Tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.

Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance.[Pubmed:28055982]

Nanotechnology. 2017 Feb 24;28(8):085603.

Herein, we prepared folate-targeting core crosslinked polymeric micelles (CCL/FA) containing multiple disulfide bonds located at the interface and core of the micelles to co-deliver doxorubicin (DOX) and the P-glycoprotein (P-gp) inhibitor Tariquidar (TQR) for reversing drug resistance. The stability and redox-responsive behavior of the CCL/FA micelles was evaluated through the changes in morphology, molecular weight and hydrodynamic size. On the one hand, the micelles possessed good stability, which led to the suppression of drug release from the CCL micelles in the physiological environment. On the other hand, under reductive conditions, the CCL micelles collapsed rapidly and accelerated drug release markedly. In vitro cytotoxicity measurements, combined with confocal laser scanning microscopy (CLSM) and flow cytometry, confirmed that the dual-drug-loaded micelles exhibited obviously higher cytotoxicity to MCF-7/ADR-resistant cells than free DOX . HCl, single-drug loaded CCL micelles and nontargeted CCL micelles. The results imply that co-delivering DOX and TQR by CCL/FA micelles may be a promising way of overcoming multidrug resistance in tumor treatments.