Biological & pharmaceutical bulletin
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Overexpression of P-glycoprotein (Pgp) and multidrug resistance protein 1 (MRP1) by tumors results in multidrug resistance (MDR) to structurally unrelated anti-tumor agents. HZ08, a chiral compound, was a newly synthesized tetraisohydroquinoline derivative to reverse Pgp and MRP1 mediated MDR. In present studies, R, S-HZ08 and their racemate reversed the resistance to adriamycin and vincristine of adriamycin-selected human leukemia (K562/ADM) cells that overexpress Pgp. ⋯ However, R, S-HZ08 and their racemate hardly affected intracellular glutathione (GSH) levels and glutathione S-transferase (GST) activities in MCF-7/ADM cells. The result showed that R, S-HZ08 and their racemate possibly reverse MDR1 mediated multidrug resistance by a direct interaction with MRP1, not interaction with MRP1 via GSH. Thus, R, S-HZ08 and their racemate should be useful for treating patients with tumors that overexpress both Pgp and MRP1.
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Several lines of evidence suggest that activation of spinal mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) and p38 MAPK, contributes to the induction and maintenance of chronic pain. We recently reported that an intrathecal (i.t.) administration of ATP evoked tactile allodynia, which lasted more than 1 week in rats. The long-lasting allodynia was induced by activation of spinal P2X 2/3-receptors, and the induction and early phase of maintenance, but not the late phase, was mediated, at least in part, by the activation of spinal glial cells. ⋯ ATP-evoked allodynia, but not the late maintenance phase (7-d post-ATP administration), while the p38 MAPK inhibitor, SB203580 (10 microg), had little effect. These results suggest that the induction phase and early maintenance phase, but not the late maintenance phase of long-lasting allodynia is mediated by the activation of ERK, rather than by the activation of p38 MAPK, in the spinal cord. These findings are informative for elucidating the mechanisms underlying the pathogenesis of chronic pain.