Tunicamycin potentiates drug cytotoxicity and vincristine retention in multidrug resistant cell lines.
Tunicamycin (TM), an inhibitor of glycoprotein processing, was investigated for its potential to reverse the multiple drug resistance (MDR) phenotype. When TM was added in vitro to drug-resistant NIH-3T3-MDR and KB-8-5-11 cells, they developed an increased sensitivity to doxorubicin, epirubicin, vincristine and colchicine. Similarly, the sensitivity of NIH-3T3-MDR cells to cisplatin was also enhanced by TM. In the presence of TM, drug-sensitive NIH-3T3-parental cells exhibited greater susceptibility to the toxic effects of doxorubicin, epirubicin, vincristine (marginally significant), and colchicine, but not to cisplatin. Tunicamycin-treated drug-sensitive KB-3-1 cells showed an increased response to vincristine, but not to the other anticancer drugs. Pretreatment with TM inhibited glycoprotein synthesis in all the cell lines. Neither prior exposure to, nor co-incubation with TM, influenced the uptake of vincristine (VCR) in the various cell lines. However, NIH-3T3-MDR cells accumulated less VCR than their drug-sensitive controls and also exhibited reduced efflux of the drug when treated with TM. There were no significant differences in the levels of intracellular VCR uptake between drug-sensitive KB-3-1 and KB-8-5-11 cells. Tunicamycin increased intracellular VCR retention in KB-8-5-11 and NIH-3T3-MDR cells, but not in NIH-3T3-parental cells. However, drug-sensitive KB-3-1 cells expressed reduced VCR retention in response to TM exposure, indicating that correlations between VCR toxicity and its retention in the presence of TM should be made with caution. The results suggest that the enhancement of intracellular VCR retention in MDR cells lines caused by TM is likely to be the result of inhibition of VCR efflux. Inhibition of glycoprotein synthesis during TM exposure may account for the changes in VCR efflux and retention observed in the MDR cell lines. The enhancement of cisplatin cytotoxicity in NIH-3T3-MDR cells after exposure to TM is an interesting observation, since it is generally believed that agents which modify the MDR phenotype do not show a sensitising effect to cisplatin. These findings may have applications in the reversal of drug resistance.
Hiss
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D
Department of Pharmacology, University of Cape Town, Medical School, South Africa.
Gabriels
G
G
Jacobs
P
P
Folb
P
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology*; D014750:Vincristine / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D006023:Glycoproteins; D009363:Neoplasm Proteins; D014415:Tunicamycin; D014750:Vincristine