Results presented in this study indicate that monensin, a Na+/H+ gradient ionophore, is by itself a potent inhibitor of proliferation of both KB parent and KB/multidrug resistant (MDR) cells. By MTT assay, the ID50 of monensin against both cell lines after a 72 h drug exposure was 0.2±0.04 μg/ml. Following a 1 h exposure of KB parent and KB/MDR cells to 0.1-10 μg/ml- monensin, [3H]thymidine, [3H]uridine, [3H]leucine incorporation into DNA, RNA, and proteins, respectively, was not inhibited, thus suggesting that the mechanism of cytotoxicity of monensin may not be mediated by a direct effect on macromolecular synthesis. In the presence of subtoxic concentrations of monensin (0.05-0.1 μg/ml), the ID50 of doxorubicin against KB/MDR cells after a 72 h drug exposure was reduced from >100 μg/ml to 45 and 18 μg/ml, respectively, while the presence of monensin did not significantly alter doxorubicin cytotoxicity against KB parent cells. In 1 h experiments, the presence of monensin (5 μg/ml) increased the intracellular accumulation of doxorubicin in KB/MDR cells by about two- to threefold but not in KB parent cells. Monensin also markedly reduced doxorubicin efflux from KB/MDR cells. Under the same conditions, monensin enhanced the cellular uptake and cytotoxicity of daunorubicin and hydroxyrubicin in KB/MDR cells but not of the lipophilic anthracycline annamycin. By alkaline elution technique, monensin (5 μg/ml) alone did not induce DNA damage in either KB parent or KB/MDR cells after 1 h of incubation and did not enhance doxorubicin-induced DNA damage in KB parent cells, whereas it significantly increased doxorubicin induced DNA double-strand breaks in KB/MDR cells. Our results indicate that reversal of MDR by monensin may be due to facilitation of drug transport and subsequent enhancement of DNA damage in MDR cells.
|Original language||English (US)|
|Number of pages||7|
|Journal||International journal of oncology|
|Publication status||Published - Jan 1 1993|
ASJC Scopus subject areas
- Cancer Research