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Reversal of etoposide resistance in non-P-glycoprotein expressing multidrug resistant tumor cell lines by novobiocin.
Cancer Res. 1993 Nov 15; 53(22):5487-93.CR

Abstract

Previous reports from this laboratory have demonstrated that novobiocin produces supraadditive cytotoxicity and increases the formation of drug-stabilized topoisomerase II-DNA covalent complexes in WEHI-3B myelomonocytic leukemia and A549 lung carcinoma cells when combined with etoposide (VP-16). Inhibition of the efflux of VP-16 by novobiocin is responsible for the increase in VP-16 accumulation, which in turn leads to increased formation of VP-16-stabilized topoisomerase II-DNA covalent complexes and increased cytotoxicity. We now report that novobiocin synergistically enhanced the sensitivity of the multidrug resistant variants, WEHI-3B/NOVO and A549(VP)28, to VP-16, causing almost complete reversal of the resistance to the epipodophyllotoxin. These two tumor cell variants are resistant to several topoisomerase II-targeted drugs, particularly VP-16, but not to Vinca alkaloids; this finding corresponds to the fact that they do not overexpress the P-glycoprotein. The effects of novobiocin in these resistant sublines are mediated through the intracellular accumulation of VP-16, resulting in an increase in the formation of lethal VP-16-induced topoisomerase II-DNA covalent complexes. In the P-glycoprotein expressing multidrug resistant HCT116(VM)34 colon carcinoma and L1210/VMDRC0.06 leukemia cell lines, the latter being transfected with the human mdr-1 gene, novobiocin did not potentiate the cytotoxic activity of VP-16 nor increase the intracellular accumulation of VP-16 and the formation of covalent complexes, whereas their normal counterparts were sensitive to the potentiating activity of novobiocin when used in combination with VP-16. These results indicate that the action of novobiocin on the intracellular transport of VP-16 is not directed at the level of the P-glycoprotein, but that the action of novobiocin is antagonized by the presence of the P-glycoprotein. Since novobiocin is a clinically available antibiotic, has numerous structural analogues available for comparative studies, and has a relatively low toxicity profile, this drug, as well as structurally related agents, would appear to have significant clinical potential in combination with an epipodophyllotoxin for the treatment of non-P-glycoprotein expressing multidrug resistant tumors.

Authors+Show Affiliations

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8106148

Citation

Rappa, G, et al. "Reversal of Etoposide Resistance in non-P-glycoprotein Expressing Multidrug Resistant Tumor Cell Lines By Novobiocin." Cancer Research, vol. 53, no. 22, 1993, pp. 5487-93.
Rappa G, Lorico A, Sartorelli AC. Reversal of etoposide resistance in non-P-glycoprotein expressing multidrug resistant tumor cell lines by novobiocin. Cancer Res. 1993;53(22):5487-93.
Rappa, G., Lorico, A., & Sartorelli, A. C. (1993). Reversal of etoposide resistance in non-P-glycoprotein expressing multidrug resistant tumor cell lines by novobiocin. Cancer Research, 53(22), 5487-93.
Rappa G, Lorico A, Sartorelli AC. Reversal of Etoposide Resistance in non-P-glycoprotein Expressing Multidrug Resistant Tumor Cell Lines By Novobiocin. Cancer Res. 1993 Nov 15;53(22):5487-93. PubMed PMID: 8106148.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal of etoposide resistance in non-P-glycoprotein expressing multidrug resistant tumor cell lines by novobiocin. AU - Rappa,G, AU - Lorico,A, AU - Sartorelli,A C, PY - 1993/11/15/pubmed PY - 1993/11/15/medline PY - 1993/11/15/entrez SP - 5487 EP - 93 JF - Cancer research JO - Cancer Res VL - 53 IS - 22 N2 - Previous reports from this laboratory have demonstrated that novobiocin produces supraadditive cytotoxicity and increases the formation of drug-stabilized topoisomerase II-DNA covalent complexes in WEHI-3B myelomonocytic leukemia and A549 lung carcinoma cells when combined with etoposide (VP-16). Inhibition of the efflux of VP-16 by novobiocin is responsible for the increase in VP-16 accumulation, which in turn leads to increased formation of VP-16-stabilized topoisomerase II-DNA covalent complexes and increased cytotoxicity. We now report that novobiocin synergistically enhanced the sensitivity of the multidrug resistant variants, WEHI-3B/NOVO and A549(VP)28, to VP-16, causing almost complete reversal of the resistance to the epipodophyllotoxin. These two tumor cell variants are resistant to several topoisomerase II-targeted drugs, particularly VP-16, but not to Vinca alkaloids; this finding corresponds to the fact that they do not overexpress the P-glycoprotein. The effects of novobiocin in these resistant sublines are mediated through the intracellular accumulation of VP-16, resulting in an increase in the formation of lethal VP-16-induced topoisomerase II-DNA covalent complexes. In the P-glycoprotein expressing multidrug resistant HCT116(VM)34 colon carcinoma and L1210/VMDRC0.06 leukemia cell lines, the latter being transfected with the human mdr-1 gene, novobiocin did not potentiate the cytotoxic activity of VP-16 nor increase the intracellular accumulation of VP-16 and the formation of covalent complexes, whereas their normal counterparts were sensitive to the potentiating activity of novobiocin when used in combination with VP-16. These results indicate that the action of novobiocin on the intracellular transport of VP-16 is not directed at the level of the P-glycoprotein, but that the action of novobiocin is antagonized by the presence of the P-glycoprotein. Since novobiocin is a clinically available antibiotic, has numerous structural analogues available for comparative studies, and has a relatively low toxicity profile, this drug, as well as structurally related agents, would appear to have significant clinical potential in combination with an epipodophyllotoxin for the treatment of non-P-glycoprotein expressing multidrug resistant tumors. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/8106148/Reversal_of_etoposide_resistance_in_non_P_glycoprotein_expressing_multidrug_resistant_tumor_cell_lines_by_novobiocin_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=8106148 DB - PRIME DP - Unbound Medicine ER -