pH-Dependent regulation of camptothecin-induced cytotoxicity and cleavable complex formation by the antimalarial agent chloroquine
Identifieur interne : 002906 ( Main/Exploration ); précédent : 002905; suivant : 002907pH-Dependent regulation of camptothecin-induced cytotoxicity and cleavable complex formation by the antimalarial agent chloroquine
Auteurs : Morten Sorensen [Danemark] ; Maxwell Sehested [Danemark] ; Peter Buhl Jensen [Danemark]Source :
- Biochemical Pharmacology [ 0006-2952 ] ; 1997.
Descripteurs français
- Pascal (Inist)
- Alcaloïde, Antagoniste, Anticancéreux, Antipaludique, Antiparasitaire, Bronchopulmonaire, Camptothécine, Carcinome petite cellule, Cassure monocaténaire, Cellule tumorale, Chloroquine, Cytotoxicité, DNA, DNA topoisomerase, Facteur milieu, Homme, In vitro, Inhibiteur enzyme, Lignée GLC2, Lignée cellulaire établie, Médicament ciblé, Prévention, pH.
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
- Alkaloid, Antagonist, Antimalarial, Antineoplastic agent, Bronchopulmonary, CLQ, CPT, Chloroquine, Cytotoxicity, DNA, DNA topoisomerase, DNA topoisomerase I, Environmental factor, Enzyme inhibitor, Established cell line, FCS, Human, In vitro, NB, Parasiticid, Prevention, SCLC, Single strand break, Small cell carcinoma, Targeted drug, Topol, Tumor cell, camptothecin, chloroquine, pH, targeting of Cytotoxicity, tumor pH.
- Teeft :
- Acid rescue, Acidic, Acidic environments, Alkaline, Alkaline elution, Assay, Band depletion, Band depletion assay, Biol chem, Camptothecin, Catalytic, Catalytic cycle, Catalytic inhibitor, Catalytic inhibitors, Catalytic process, Cell doublings, Cell line, Chloroquine, Cleavable, Clonogenic assay, Control cells, Cytotoxic effect, Cytotoxicity, Dimethyl sulfoxide, Elsevier science, Ethidium bromide, Extracellular, Fetal calf serum, Final volume, Full effect, Full protection, Inhibitor, Minor modifications, Molecular weight marker, Normal tissue, Nucleic acids, Open circle, Plasmid, Response rates, Sigma chemical, Soft agar, Solid tumors, Sorensen, Strand breaks, Such regulation, Supercoiled, Topo1, Topoisomerase, Toxicity, Tumor cells, Weak base, Weak base properties, Whole cells.
Abstract
Abstract: Two classes of drugs interact with DNA topoisomerase (topo) I, namely topoi poisons such as the camptothecins, which create DNA single-strand breaks and the catalytic inhibitors, which do not. Here, we demonstrate that the antimalarial agent chloroquine is a catalytic inhibitor of eukaryote topoi, as the drug inhibited topol-mediated DNA relaxation. Chloroquine is known to be a topoll catalytic inhibitor and as such is able to inhibit the activity of a topoll poison, i.e. etoposide. We now show that chloroquine also inhibits the topoi poison camptothecin as camptothecin-stimulated nicking of plasmid DNA was inhibited by chloroquine. These observations also apply to endogenous topoi in whole cells. Accordingly, camptothecin-induced single-strand breaks as well as Cytotoxicity were antagonised by chloroquine. Further, in a band depletion assay in whole cells, chloroquine prevented camptothecin-mediated topoi trapping, indicating that chloroquine inhibits topoi by interfering with the DNA binding step of the enzyme. In contrast to camptothecin, chloroquine is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. This leads to the possibility of directing Cytotoxicity to solid tumors with low extracellular pH by combining a neutral anticancer agent, i.e. camptothecin with a weak base antagonist, i.e. chloroquine. To test the feasibility of this principle, we investigated the drug combination at varying extracellular pH. We found that the antagonising effect of chloroquine on camptothecin-mediated trapping of topol and DNA single-strand break formation was abolished at acidic extracellular pH. In a clonogenic assay, camptothecin in combination with chloroquine selectively killed cells at low pH (6.2), while camptothecin Cytotoxicity was antagonised by chloroquine at normal pH (7.2). In conclusion, we show that the topoi catalytic inhibitor chloroquine inhibits camptothecin and that chloroquine can target the cytotoxic effect of camptothecin to tumor cells in acidic environments.
Url:
DOI: 10.1016/S0006-2952(97)80318-8
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en">Abstract: Two classes of drugs interact with DNA topoisomerase (topo) I, namely topoi poisons such as the camptothecins, which create DNA single-strand breaks and the catalytic inhibitors, which do not. Here, we demonstrate that the antimalarial agent chloroquine is a catalytic inhibitor of eukaryote topoi, as the drug inhibited topol-mediated DNA relaxation. Chloroquine is known to be a topoll catalytic inhibitor and as such is able to inhibit the activity of a topoll poison, i.e. etoposide. We now show that chloroquine also inhibits the topoi poison camptothecin as camptothecin-stimulated nicking of plasmid DNA was inhibited by chloroquine. These observations also apply to endogenous topoi in whole cells. Accordingly, camptothecin-induced single-strand breaks as well as Cytotoxicity were antagonised by chloroquine. Further, in a band depletion assay in whole cells, chloroquine prevented camptothecin-mediated topoi trapping, indicating that chloroquine inhibits topoi by interfering with the DNA binding step of the enzyme. In contrast to camptothecin, chloroquine is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. This leads to the possibility of directing Cytotoxicity to solid tumors with low extracellular pH by combining a neutral anticancer agent, i.e. camptothecin with a weak base antagonist, i.e. chloroquine. To test the feasibility of this principle, we investigated the drug combination at varying extracellular pH. We found that the antagonising effect of chloroquine on camptothecin-mediated trapping of topol and DNA single-strand break formation was abolished at acidic extracellular pH. In a clonogenic assay, camptothecin in combination with chloroquine selectively killed cells at low pH (6.2), while camptothecin Cytotoxicity was antagonised by chloroquine at normal pH (7.2). In conclusion, we show that the topoi catalytic inhibitor chloroquine inhibits camptothecin and that chloroquine can target the cytotoxic effect of camptothecin to tumor cells in acidic environments.</div>
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