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Roles of volume-sensitive Cl- channel in cisplatin-induced apoptosis in human epidermoid cancer cells
1Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan.
Abstract:
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.
Insights
Cisplatin-induced cancer cell death involves chloride channel activity. Blocking these channels with DIDS reduces cisplatin
Area of Science:
- Cell Biology
- Molecular Pharmacology
- Cancer Research
Background:
- Cisplatin is a chemotherapy drug that triggers apoptosis (programmed cell death) by damaging DNA.
- Stilbene derivatives like SITS can confer cisplatin resistance, independent of intracellular pH or extracellular bicarbonate.
- The role of chloride (Cl-) channels in cisplatin's mechanism of action and resistance is not fully understood.
Purpose of the Study:
- To investigate the relationship between cisplatin-induced apoptosis and chloride channel activity in human adenocarcinoma KB cells.
- To determine if DIDS, a stilbene derivative, affects cisplatin-induced cell death and resistance.
- To characterize the chloride channels involved in KB cells and their response to cisplatin.
Main Methods:
- Human adenocarcinoma KB cells were treated with cisplatin and/or DIDS.
- Caspase-3 activation and cell death were measured over 18 hours.
- Cell sensitivity to a 5-day cisplatin exposure was assessed.
- Whole-cell patch-clamp recordings were used to analyze chloride channel activity.
- KB cells were pretreated with cisplatin before patch-clamp analysis.
Main Results:
- DIDS significantly reduced cisplatin-induced caspase-3 activation and cell death.
- DIDS treatment decreased KB cell sensitivity to prolonged cisplatin exposure.
- KB cells express functional volume-sensitive outwardly rectifying (VSOR) Cl- channels that are sensitive to DIDS.
- Cisplatin pretreatment for 12 hours enhanced the activity of these VSOR Cl- channels.
Conclusions:
- Cisplatin-induced cytotoxicity in KB cells is linked to increased activity of DIDS-sensitive VSOR Cl- channels.
- Blockade of these VSOR Cl- channels by stilbene derivatives contributes to cisplatin resistance.
- Targeting VSOR Cl- channels may offer a strategy to overcome cisplatin resistance in cancer therapy.
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