The multidrug resistance is an obstacle in the chemotherapy treatment (such as doxorubicin, vincristine, paclitaxel, TKIs) for many solid and haematological tumours. Many factors can cause the multidrug resistance. Among them, the overexpression of P-gp (ABCB1), an ATP-binding cassette (ABC) drug efflux transporter, on the surface of resistant cells is considered as a key factor mediating multidrug resistance. Zosuquidar Trihydrochloride is the trihydrochloride form of Zosuquidar. Zosuquidar is P-gp modulator that inhibited Pgp-ATPase activity 50-60% at 2 and 10μM and had no effect at 0.08 and 0.4μM (measured by P-gp ATPase activity). However, the modulator activity of Zosuquidar is not dependent on inhibition of the ATPase activity associated with P-gp. Zosuquidar works both in vitro and in vivo. Combined treatment with Zosuquidar at 0.1μM could fully restored sensitivity of CEM/VLB100 cells to vinblastine, doxorubicin, etoposide and Taxol, and showed a prolonged effect up to 24h at concentration of 0.5μM in cytotoxicity assay of doxorubicin. The effect of Zosuquidar on restoring sensitivity of different compound may due to its blocking the affinity of compound to cell plasma membranes P-gp and competitively inhibited equilibrium binding of compound to P-gp (Ki=~60nM). Co-administration of Zosuquidar (20mg/kg, i.v.) with doxorubicin or etoposide significantly increased the life span of mice bearing P388/ADR murine leukemia cells, compared with group treated with agent alone. Also Zosuquidar (30mg/kg) enhanced the antitumor activity of Taxol in a multidrug-resistant human non-small cell lung carcinoma nude mouse xenograft model. However this in vivo increased life span achieved by Zosuquidar was lack of effect on pharmacokinetics[1].
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