Molecular pharmacology
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Molecular pharmacology · Jun 2009
Enhancement of doxorubicin cytotoxicity on human esophageal squamous cell carcinoma cells by indomethacin and 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC236) via inhibiting P-glycoprotein activity.
Doxorubicin is a chemotherapeutic drug widely used for the treatment of advanced esophageal squamous cell carcinoma. However, its efficacy is usually limited by the development of multidrug resistance (MDR), which has been linked to the up-regulation of P-glycoprotein (P-gp) in cancer cells. Conventional nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 (COX-2)-selective inhibitors have been demonstrated to overcome MDR in some cancer cells. ⋯ To this end, we observed that indomethacin and SC236 directly functioned as noncompetitive inhibitors of P-gp, which were manifested as a reduction of P-gp ATPase activity. Collectively, these findings suggest that the direct inhibitory effects of indomethacin and SC236 on P-gp may contribute to their ability to increase the intracellular retention of doxorubicin and thus enhance its cytotoxicity. The combination of indomethacin or SC236 with doxorubicin may have significant potential clinical application, especially in the circumvention of P-gp-mediated MDR in cancer cells.
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Molecular pharmacology · Jun 2009
Activation and modulation of concatemeric GABA-A receptors expressed in human embryonic kidney cells.
We have employed whole-cell and single-channel electrophysiology to examine the kinetic and pharmacological properties of GABA-A receptors consisting of gamma2L-beta2-alpha1 and beta2-alpha1 subunit concatemeric constructs expressed in human embryonic kidney cells. Concatemeric receptors activated by GABA exhibited the same single-channel conductance, channel opening rate constant, and basic open- and closed-time properties as receptors containing free subunits. However, the whole-cell GABA dose-response and the single-channel effective opening rate curves were shifted to higher GABA concentrations, suggesting that the concatemeric receptors have a lower affinity to GABA. ⋯ We infer that a single wild-type alpha subunit is capable of mediating the full set of kinetic effects in the presence of steroids. Introduction of the alpha1Q241W mutation, previously shown to mimic the effect of the steroid on alpha1beta2gamma2L channels, selectively into either concatemeric construct altered the mode of activity elicited by P4S, but the presence of mutations in both alpha subunits was required to affect open-time distributions. The data indicate that the alpha1Q241W mutation acts as a partial steroid modulator.