Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells
Identifieur interne : 002B58 ( Main/Exploration ); précédent : 002B57; suivant : 002B59Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells
Auteurs : Toshiro Takatori [Japon] ; Takeshi Koizumi [Japon] ; Taro Tokui [Japon] ; Yoshihiro Mitsuhashi [Japon] ; Akio Shiraishi [Japon] ; Takashi Tsuruo [Japon]Source :
- Cancer Chemotherapy and Pharmacology [ 0344-5704 ] ; 1995-07-01.
English descriptors
- KwdEn :
- Teeft :
- Antitumor, Antitumor effects, Candida cylindracea, Cell line, Cell lines, Cellular homogenate, Chloroquine, Cholesterol esterase, Cholesterol esterase activity, Crude membrane, Crude membrane fraction, Cytosol, Cytosol fraction, Cytotoxic, Cytotoxic action, Cytotoxic effect, Cytotoxicity, Esterase, Homogenate, Icso, Icso value, Icso values, Initial cell density, Inoculum size, Lysosomal function, Lysosome, Macrocyclic lactone antibiotics, Membrane fraction, Rhizoxin, Same mode, Tsuruo, Tubulin, Tumor cells, Various concentrations.
Abstract
Abstract: RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.
Url:
DOI: 10.1007/BF00689446
Affiliations:
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type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Mitsuhashi, Yoshihiro" sort="Mitsuhashi, Yoshihiro" uniqKey="Mitsuhashi Y" first="Yoshihiro" last="Mitsuhashi">Yoshihiro Mitsuhashi</name><affiliation wicri:level="3"><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Shiraishi, Akio" sort="Shiraishi, Akio" uniqKey="Shiraishi A" first="Akio" last="Shiraishi">Akio Shiraishi</name><affiliation wicri:level="3"><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Tsuruo, Takashi" sort="Tsuruo, Takashi" uniqKey="Tsuruo T" first="Takashi" last="Tsuruo">Takashi Tsuruo</name><affiliation wicri:level="4"><country xml:lang="fr">Japon</country><wicri:regionArea>Institute of Molecular and Cellular Bioscience, University of Tokyo, Yayoi, Bunkyo-ku, 113, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author></analytic><monogr></monogr><series><title level="j">Cancer Chemotherapy and Pharmacology</title><title level="j" type="abbrev">Cancer Chemother. Pharmacol.</title><idno type="ISSN">0344-5704</idno><idno type="eISSN">1432-0843</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="1995-07-01">1995-07-01</date><biblScope unit="volume">35</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="283">283</biblScope><biblScope unit="page" to="290">290</biblScope></imprint><idno type="ISSN">0344-5704</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0344-5704</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cytotoxicity</term><term>RS-1541</term><term>Rhizoxin</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Antitumor</term><term>Antitumor effects</term><term>Candida cylindracea</term><term>Cell line</term><term>Cell lines</term><term>Cellular homogenate</term><term>Chloroquine</term><term>Cholesterol esterase</term><term>Cholesterol esterase activity</term><term>Crude membrane</term><term>Crude membrane fraction</term><term>Cytosol</term><term>Cytosol fraction</term><term>Cytotoxic</term><term>Cytotoxic action</term><term>Cytotoxic effect</term><term>Cytotoxicity</term><term>Esterase</term><term>Homogenate</term><term>Icso</term><term>Icso value</term><term>Icso values</term><term>Initial cell density</term><term>Inoculum size</term><term>Lysosomal function</term><term>Lysosome</term><term>Macrocyclic lactone antibiotics</term><term>Membrane fraction</term><term>Rhizoxin</term><term>Same mode</term><term>Tsuruo</term><term>Tubulin</term><term>Tumor cells</term><term>Various concentrations</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.</div></front></TEI><affiliations><list><country><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement><orgName><li>Université de Tokyo</li></orgName></list><tree><country name="Japon"><region name="Région de Kantō"><name sortKey="Takatori, Toshiro" sort="Takatori, Toshiro" uniqKey="Takatori T" first="Toshiro" last="Takatori">Toshiro Takatori</name></region><name sortKey="Koizumi, Takeshi" sort="Koizumi, Takeshi" uniqKey="Koizumi T" first="Takeshi" last="Koizumi">Takeshi Koizumi</name><name sortKey="Mitsuhashi, Yoshihiro" sort="Mitsuhashi, Yoshihiro" uniqKey="Mitsuhashi Y" first="Yoshihiro" last="Mitsuhashi">Yoshihiro Mitsuhashi</name><name sortKey="Shiraishi, Akio" sort="Shiraishi, Akio" uniqKey="Shiraishi A" first="Akio" last="Shiraishi">Akio Shiraishi</name><name sortKey="Takatori, Toshiro" sort="Takatori, Toshiro" uniqKey="Takatori T" first="Toshiro" last="Takatori">Toshiro Takatori</name><name sortKey="Tokui, Taro" sort="Tokui, Taro" uniqKey="Tokui T" first="Taro" last="Tokui">Taro Tokui</name><name sortKey="Tsuruo, Takashi" sort="Tsuruo, Takashi" uniqKey="Tsuruo T" first="Takashi" last="Tsuruo">Takashi Tsuruo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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