Asaumi J I, Kawasaki S, Gao X S, Kuroda M, Hiraki Y
Department of Radiology, Okayama University Medical School, Japan.
Anticancer Res. 1996 Mar-Apr;16(2):725-8.
Intracellular accumulation of adriamycin (ADR) has been reported to be influenced by cell membrane potential. We first evaluated intracellular accumulation of ADR and 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, and found a good correlation between ADR and NK-2280 intracellular accumulation in several cell lines. This suggests that ADR accumulation may be influenced by cell membrane potential or the mechanisms of NK-2280 accumulation may be similar to those of ADR accumulation. Next, we observed the influence of the NA+/H+ exchanger and Cl-/HCO3- exchanger on the intracellular accumulation of ADR and NK-2280, and found that ADR accumulation decreased with increasing concentrations of 3,5-diamino-6-chloro-N-(diaminomethylene)pyrazinecarboxamide (amiloride), an inhibitor of the Na+/H+ exchanger, and 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS), an inhibitor of the Cl-/HCO3- exchanger, however, NK-2280 accumulation was increased by amiloride, and decreased by DIDS. The increased accumulation of NK-2280 induced by amiloride may be due to the increased cell membrane potential caused by the inhibition of H+ ion efflux and NA+ ion influx due to the inhibition of the Na+/H+ exchanger. The decreased accumulation of NK-2280 may be also due to the decreased cell membrane potential caused by the inhibition of Cl- ion efflux due to the inhibition of the Cl-/HCO3- exchanger by DIDS. However, the decreased rate caused by DIDS was greater than the increased rate caused by amiloride. Therefore, it is suggested that the decreased accumulation of NK-2280 by DIDS may be influenced by other factors apart from cell membrane potential. These results suggest that the Cl-/HCO3- exchanger may be related to both ADR accumulation, and NK-2280 accumulation, and that the Na+/H+ exchanger may be related to ADR accumulation, but not NK-2280. This suggests that the Cl-/HCO3- exchanger is of low selectivity.
据报道，阿霉素（ADR）的细胞内蓄积受细胞膜电位影响。我们首先评估了ADR和3,3'-（二正己基）-2,2'-氧杂羰花青碘化物（NK-2280，一种细胞膜电位指示剂）的细胞内蓄积情况，发现在几种细胞系中ADR与NK-2280的细胞内蓄积之间存在良好的相关性。这表明ADR的蓄积可能受细胞膜电位影响，或者NK-2280蓄积的机制可能与ADR蓄积的机制相似。接下来，我们观察了Na⁺/H⁺交换体和Cl⁻/HCO₃⁻交换体对ADR和NK-2280细胞内蓄积的影响，发现随着Na⁺/H⁺交换体抑制剂3,5-二氨基-6-氯-N-（二氨基亚甲基）吡嗪甲酰胺（氨氯吡咪）以及Cl⁻/HCO₃⁻交换体抑制剂4,4'-二异硫氰酸根合芪-2,2'-二磺酸（DIDS）浓度的增加，ADR的蓄积减少。然而，氨氯吡咪使NK-2280的蓄积增加，而DIDS使其减少。氨氯吡咪诱导的NK-2280蓄积增加可能是由于Na⁺/H⁺交换体受抑制，导致H⁺离子外流和Na⁺离子内流受抑制，从而使细胞膜电位升高所致。NK-2280蓄积减少也可能是由于DIDS抑制Cl⁻/HCO₃⁻交换体，导致Cl⁻离子外流受抑制，进而使细胞膜电位降低所致。然而，DIDS导致的降低速率大于氨氯吡咪导致的升高速率。因此，提示DIDS导致的NK-2280蓄积减少可能受细胞膜电位以外的其他因素影响。这些结果表明，Cl⁻/HCO₃⁻交换体可能与ADR蓄积以及NK-2280蓄积均有关，而Na⁺/H⁺交换体可能与ADR蓄积有关，但与NK-2280无关。这表明Cl⁻/HCO₃⁻交换体的选择性较低。
