Roles of volume-sensitive Cl- channel in cisplatin-induced apoptosis in human epidermoid cancer cells
Roles of volume-sensitive Cl- channel in cisplatin-induced apoptosis in human epidermoid cancer cells
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DOI：
10.1007/s00232-005-0779-y
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发表时间：
2005-06-01
影响因子：
2.4
通讯作者：
Okada, Y
中科院分区：
文献类型：
--
作者：
Ise, T;Shimizu, T;Okada, Y
抗癌药物顺铂通过损伤DNA诱导细胞凋亡。由于芪衍生物的Cl-/HCO 3-交换和Cl-通道，SITS，阻断剂，已知诱导顺铂耐药的方式独立于细胞内pH值和细胞外HCO 3，我们研究了顺铂诱导的细胞凋亡和Cl-通道活性之间的关系在人腺癌KB细胞。芪衍生物，DIDS，减少顺铂诱导的caspase-3激活和细胞死亡，这是检测到超过18小时后，顺铂治疗。还发现DIDS降低KB细胞对顺铂暴露5天的敏感性。全细胞膜片钳记录显示KB细胞功能性表达体积敏感性外向整流（VSOR）Cl通道，该通道被渗透性细胞肿胀激活并对DIDS敏感。顺铂预处理12 h可使VSOR Cl-电流增加.因此，可以得出结论，顺铂诱导的KB细胞的细胞毒性与增加的活性的DIDS敏感的VSOR Cl-通道，该通道的封锁是，至少部分地，负责由芪衍生物诱导的顺铂耐药性。
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) Clchannels 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.