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Swelling-activated chloride channels in multidrug-sensitive and -resistant cells
G R Ehring1, Y V Osipchuk, M D Cahalan
1Department of Physiology and Biophysics, University of California at Irvine 92717.
The Journal of General Physiology
|December 1, 1994
Summary
Multidrug resistance in cancer cells is often linked to P-glycoprotein drug efflux pumps. This study found that swelling-activated chloride channels function independently of P-glycoprotein, showing distinct pharmacological properties.
Area of Science:
- Cellular and Molecular Biology
- Pharmacology
- Oncology
Background:
- Chemotherapeutic resistance in cancer is frequently mediated by P-glycoprotein, a membrane protein that pumps drugs out of cells.
- Understanding the interplay between drug resistance mechanisms and other cellular transport systems is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the functional relationship between P-glycoprotein-mediated drug efflux and swelling-activated chloride channels in drug-sensitive and multidrug-resistant cell lines.
- To determine if these two transport systems are interdependent or operate independently.
Main Methods:
- Utilized patch clamp and video-imaging techniques to assess P-glycoprotein expression and function.
- Employed rhodamine-123 (R123) efflux assays and SPQ fluorescent probe imaging to monitor drug transport and chloride channel activity.
- Compared drug-sensitive (NIH-3T3, 8226 myeloma) and multidrug-resistant (MDR1-transfectant, 8226/Dox40) cell lines.
Main Results:
- Resistant cell lines exhibited high P-glycoprotein expression and rapid R123 efflux, while control cells did not.
- Cell swelling activated chloride channels (gCl) in all tested cell lines, with similar induction rates and biophysical properties between sensitive and resistant cells.
- Pharmacological profiling revealed distinct sensitivities: chloride channels were blocked by DIDS, NPPB, and tamoxifen, whereas verapamil selectively inhibited R123 efflux, with no overlap in blockers affecting both systems.
Conclusions:
- P-glycoprotein and swelling-activated chloride channels are functionally independent and separable systems in neoplastic cells.
- Their distinct pharmacological profiles suggest independent roles in cellular physiology and potential for targeted therapeutic strategies.