Ise T, Shimizu T, Lee E L, Inoue H, Kohno K, Okada Y
Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan.
J Membr Biol. 2005 Jun;205(3):139-45. doi: 10.1007/s00232-005-0779-y.
The anti-cancer drug cisplatin induces apoptosis by damaging DNA. Since a stilbene-derivative blocker of Cl-/HCO3- exchangers and Cl- channels, SITS, is known to induce cisplatin resistance in a manner independent of intracellular pH and extracellular HCO3-, we investigated the relation between cisplatin-induced apoptosis and Cl- channel activity in human adenocarcinoma KB cells. A stilbene derivative, DIDS, reduced cisplatin-induced caspase-3 activation and cell death, which were detected over 18 h after treatment with cisplatin. DIDS was also found to reduce sensitivity of KB cells to 5-day exposure to cisplatin. Whole-cell patch-clamp recordings showed that KB cells functionally express volume-sensitive outwardly rectifying (VSOR) Cl- channels which are activated by osmotic cell swelling and sensitive to DIDS. Pretreatment of the cells with cisplatin for 12 h augmented the magnitude of VSOR Cl- current. Thus, it is concluded that cisplatin-induced cytotoxicity in KB cells is associated with augmented activity of a DIDS-sensitive VSOR Cl- channel and that blockade of this channel is, at least in part, responsible for cisplatin resistance induced by a stilbene derivative.
抗癌药物顺铂通过损伤DNA诱导细胞凋亡。由于已知一种二苯乙烯衍生物——Cl⁻/HCO₃⁻交换体和Cl⁻通道的阻滞剂SITS，能以一种独立于细胞内pH和细胞外HCO₃⁻的方式诱导顺铂耐药，我们研究了顺铂诱导的细胞凋亡与人类腺癌KB细胞中Cl⁻通道活性之间的关系。一种二苯乙烯衍生物DIDS，可降低顺铂诱导的caspase-3激活和细胞死亡，这些在顺铂处理18小时后即可检测到。还发现DIDS可降低KB细胞对顺铂5天暴露的敏感性。全细胞膜片钳记录显示，KB细胞功能性表达容积敏感性外向整流（VSOR）Cl⁻通道，该通道由渗透性细胞肿胀激活且对DIDS敏感。用顺铂预处理细胞12小时可增强VSOR Cl⁻电流的幅度。因此，得出结论，顺铂诱导的KB细胞毒性与DIDS敏感的VSOR Cl⁻通道活性增强有关，并且该通道的阻断至少部分地导致了二苯乙烯衍生物诱导的顺铂耐药。
