ヒト白血病K562細胞でクロトリマゾールにより誘発される細胞死に対するマイクロモル濃度の亜鉛の影響

Our recent study showed that the simultaneous application of clotrimazole with CdCI2 or PbCI2 exerted potent cytotoxic action in rat thymocytes although respective agents were ineffective. It was also the case of ZnCl2 and clotrimazole in preliminary study using rat thymocytes. Since clotrimazole is supposed to be a candidate for anticancer drug, we examined the effects of clotrimazole, ZnCI2, and their combination on human leukemia K562 cells. The combination of clotrimazole and ZnCl2 exerted potent cytotoxic effects on the growth and lethality of K562 cells by presumably modifying the process of cell death. The result suggests the possibility that endogenous Zn2+ may modify the action of clotrimazole

ヒト白血病K562細胞におけるアドリアマイシン作用のクレモフォールELによる修飾

Adriamycin and paclitaxel are simultaneously used for cancer treatment in some cases. The formula of paclitaxel contains cremophor EL as a solvent. Since this solvent exerts diverse biological actions, the modification of adriamycin action by cremophor EL has been studied on human leukemia K562 cells. Cremophor EL did not significantly affect the concentration-response relation for antiproliferative action of adriamycin and the cell cycle changed by adriamycin. However, the induction of morphological change by adriamycin was significantly augmented by cremophor EL. The simultaneous application of cremophor EL increased the intensity of fluorescence from adriamycin trapped inside the cells in a concentration-dependent manner, suggesting an increase in intracellular concentration of adriamycin by cremophor EL. Adriamycin alone at concentrations higher than those to completely inhibit the growth induced morphological change in K562 cells. Therefore, cremophor EL may potentiate some of actions induced by adriamycin when adriamycin and paclitaxel are simultaneously applied

Effects of Zn2+ chelators, DTPA and TPEN, and ZnCl2 on the cells treated with hydrogen peroxide: a flow-cytometric study using rat thymocytes

Recently, we have revealed that trace Zn2+ partly attenuates Ca2+-dependent cell death induced by A23187, a calcium ionophore, in rat thymocytes. In this study, to see if Zn2+ attenuates the H2O2-induced cell death that is also Ca2+-dependent, the effects of ZnCl2 and chelators for Zn2+ have been examined by using a flowcytometer with propidium iodide. The incubation with H2O2 increased the cell lethality. Simultaneous application of ZnCl2 greatly augmented the H2O2-induced increase in lethality. DTPA, a chelator for extracellular Zn2+, did not affect the increase in cell lethality by H2O2. However, the H2O2-induced increase in cell lethality was greatly attenuated by TPEN, a chelator for extracellular and intracellular Zn2+. Taken together, it may be likely that intracellular Zn2+ modifies the H2O2-induced cytotoxicity. However, it cannot be ruled out the possibility that TPEN chelates intracellular Fe2+, resulting in inhibiting the formation of hydroxyl radical from H2O2 that leads to an attenuation of H2O2 cytotoxicity

Effect of econazole on membrane calcium transport in rat thymocytes

Econazole, one of azole antifungals, is proven to exhibit an inhibitory action on Mycobaterium tuberculosis and its multidrug-resistant strains under in vitro and ex vivo conditions. However, econazole has been used as a pharmacological tool for inhibiting capacitative Ca2+ influx and exerts multiple effects on cellular Ca2+ circumstance. Therefore, to suggest the toxic effect of econazole at therapeutic concentrations, we have tested on the effect on membrane Ca2+ transport in rat thymocytes by using a flow cytometer with Fluo-3, an indicator of intracellular Ca2+. Econazole at concentrations of 1-3 μM increased membrane Ca2+ permeability and inhibited capacitative Ca2+ influx without affecting passive Ca2+ influx, Ca2+ release from intracellular Ca2+ store sites, and membrane Ca2+ pump. Econazole at 0.3 μM, a therapeutic concentration against tuberculosis caused by multidrug-resistant and latent M. tuberculosis, did not affect membrane Ca2+ transport. It may be suggested that econazole at therapeutic concentrations exerts no side effect related to Ca2+