Abstract
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) |
|---|---|
| Pages (from-to) | 971-977 |
| Number of pages | 7 |
| Journal | International Journal of Oncology |
| Volume | 3 |
| Issue number | 5 |
| State | Published - 1993 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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Intrinsic cytotoxicity and reversal of multidrug-resistance by monensin in KB parent and MDR cells. / Ling, Y. H.; Priebe, W.; Perez-Soler, Roman.
In: International Journal of Oncology, Vol. 3, No. 5, 1993, p. 971-977.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Intrinsic cytotoxicity and reversal of multidrug-resistance by monensin in KB parent and MDR cells
AU - Ling, Y. H.
AU - Priebe, W.
AU - Perez-Soler, Roman
PY - 1993
Y1 - 1993
N2 - 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.
AB - 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.
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M3 - Article
VL - 3
SP - 971
EP - 977
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 5
ER -