Roles of volume-sensitive Cl- channel in cisplatin-induced apoptosis in human epidermoid cancer cells.
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.
Ise
T
T
Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan.
Shimizu
T
T
Lee
E L
EL
Inoue
H
H
Kohno
K
K
Okada
Y
Y
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D010693:Phloretin / Q000494:pharmacology
D018118:Chloride Channels; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002945:Cisplatin; D010693:Phloretin