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Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance
K Sakata1, T T Kwok, B J Murphy
1Laboratory of Cell and Molecular Biology, Life Sciences Division SRI International, Menlo Park, California 94025.
Abstract:
In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance.
Insights
Hypoxia can induce drug resistance in cancer cells, but this resistance differs from P-glycoprotein mediated multidrug resistance (MDR). Hypoxia-induced resistance is transient and not linked to P-glycoprotein expression.
Area of Science:
- Oncology
- Cancer Biology
- Drug Resistance Mechanisms
Background:
- Hypoxia, a common feature in solid tumors, is increasingly recognized as a driver of therapeutic resistance.
- P-glycoprotein (P-gp) mediated multidrug resistance (MDR) is a well-established mechanism of cancer drug resistance.
- The relationship between hypoxia and MDR, particularly concerning P-gp, requires further elucidation.
Purpose of the Study:
- To investigate hypoxia-induced drug resistance in cancer cells.
- To compare hypoxia-induced drug resistance with P-glycoprotein associated multidrug resistance (MDR).
- To determine the characteristics and potential mechanisms of hypoxia-induced drug resistance.
Main Methods:
- EMT6/Ro cells were exposed to various chemotherapeutic drugs (adriamycin, 5-fluorouracil, actinomycin D, colchicine, vincristine, cisplatin) under hypoxic conditions.
- Drug resistance was assessed immediately after hypoxic treatment and after reoxygenation.
- Drug efflux and P-glycoprotein mRNA expression were analyzed in hypoxia-treated and aerobic cells.
Main Results:
- Hypoxia-treated cells developed transient resistance to adriamycin, 5-fluorouracil, and actinomycin D, which was lost upon reoxygenation.
- No resistance was observed against colchicine, vincristine, or cisplatin following hypoxic treatment.
- No correlation was found between adriamycin content and hypoxia-induced resistance, nor were differences observed in adriamycin efflux.
- P-glycoprotein mRNA was not detected in hypoxia-treated cells, suggesting a non-P-gp mediated resistance mechanism.
Conclusions:
- Hypoxia-induced drug resistance is a distinct phenomenon separate from P-glycoprotein associated MDR.
- The mechanisms underlying hypoxia-induced resistance do not involve P-glycoprotein.
- This finding has implications for understanding and overcoming therapeutic resistance in hypoxic tumors.