Chloroquine-Mediated Lysosomal Dysfunction Enhances the Anticancer Effect of Nutrient Deprivation
Identifieur interne : 001415 ( Main/Exploration ); précédent : 001414; suivant : 001416Chloroquine-Mediated Lysosomal Dysfunction Enhances the Anticancer Effect of Nutrient Deprivation
Auteurs : Ljubica Harhaji-Trajkovic [Serbie] ; Katarina Arsikin [Serbie] ; Tamara Kravic-Stevovic [Serbie] ; Sasa Petricevic [Serbie] ; Gordana Tovilovic [Serbie] ; Aleksandar Pantovic [Serbie] ; Nevena Zogovic [Serbie] ; Biljana Ristic [Serbie] ; Kristina Janjetovic [Serbie] ; Vladimir Bumbasirevic [Serbie] ; Vladimir Trajkovic [Serbie]Source :
- Pharmaceutical Research [ 0724-8741 ] ; 2012-08-01.
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Abstract
ABSTRACT: Purpose: To investigate the ability of chloroquine, a lysosomotropic autophagy inhibitor, to enhance the anticancer effect of nutrient deprivation. Methods: Serum-deprived U251 glioma, B16 melanoma and L929 fibrosarcoma cells were treated with chloroquine in vitro. Cell viability was measured by crystal violet and MTT assay. Oxidative stress, apoptosis/necrosis and intracellular acidification were analyzed by flow cytometry. Cell morphology was examined by light and electron microscopy. Activation of AMP-activated protein kinase (AMPK) and autophagy were monitored by immunoblotting. RNA interference was used for AMPK and LC3b knockdown. The anticancer efficiency of intraperitoneal chloroquine in calorie-restricted mice was assessed using a B16 mouse melanoma model. Results: Chloroquine rapidly killed serum-starved cancer cells in vitro. This effect was not mimicked by autophagy inhibitors or LC3b shRNA, indicating autophagy-independent mechanism. Chloroquine-induced lysosomal accumulation and oxidative stress, leading to mitochondrial depolarization, caspase activation and mixed apoptotic/necrotic cell death, were prevented by lysosomal acidification inhibitor bafilomycin. AMPK downregulation participated in chloroquine action, as AMPK activation reduced, and AMPK shRNA mimicked chloroquine toxicity. Chloroquine inhibited melanoma growth in calorie-restricted mice, causing lysosomal accumulation, mitochondrial disintegration and selective necrosis of tumor cells. Conclusion: Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy.
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DOI: 10.1007/s11095-012-0753-1
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xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000, Belgrade</wicri:regionArea><wicri:noRegion>Belgrade</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Serbie</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Pharmaceutical Research</title><title level="j" type="sub">An Official Journal of the American Association of Pharmaceutical Scientists</title><title level="j" type="abbrev">Pharm Res</title><idno type="ISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><imprint><publisher>Springer US; http://www.springer-ny.com</publisher><pubPlace>Boston</pubPlace><date type="published" when="2012-08-01">2012-08-01</date><biblScope unit="volume">29</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="2249">2249</biblScope><biblScope unit="page" to="2263">2263</biblScope></imprint><idno type="ISSN">0724-8741</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0724-8741</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AMPK</term><term>autophagy</term><term>caloric restriction</term><term>cancer</term><term>chloroquine</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">ABSTRACT: Purpose: To investigate the ability of chloroquine, a lysosomotropic autophagy inhibitor, to enhance the anticancer effect of nutrient deprivation. Methods: Serum-deprived U251 glioma, B16 melanoma and L929 fibrosarcoma cells were treated with chloroquine in vitro. Cell viability was measured by crystal violet and MTT assay. Oxidative stress, apoptosis/necrosis and intracellular acidification were analyzed by flow cytometry. Cell morphology was examined by light and electron microscopy. Activation of AMP-activated protein kinase (AMPK) and autophagy were monitored by immunoblotting. RNA interference was used for AMPK and LC3b knockdown. The anticancer efficiency of intraperitoneal chloroquine in calorie-restricted mice was assessed using a B16 mouse melanoma model. Results: Chloroquine rapidly killed serum-starved cancer cells in vitro. This effect was not mimicked by autophagy inhibitors or LC3b shRNA, indicating autophagy-independent mechanism. Chloroquine-induced lysosomal accumulation and oxidative stress, leading to mitochondrial depolarization, caspase activation and mixed apoptotic/necrotic cell death, were prevented by lysosomal acidification inhibitor bafilomycin. AMPK downregulation participated in chloroquine action, as AMPK activation reduced, and AMPK shRNA mimicked chloroquine toxicity. Chloroquine inhibited melanoma growth in calorie-restricted mice, causing lysosomal accumulation, mitochondrial disintegration and selective necrosis of tumor cells. Conclusion: Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy.</div></front></TEI><affiliations><list><country><li>Serbie</li></country></list><tree><country name="Serbie"><noRegion><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name></noRegion><name sortKey="Arsikin, Katarina" sort="Arsikin, Katarina" uniqKey="Arsikin K" first="Katarina" last="Arsikin">Katarina Arsikin</name><name sortKey="Bumbasirevic, Vladimir" sort="Bumbasirevic, Vladimir" uniqKey="Bumbasirevic V" first="Vladimir" last="Bumbasirevic">Vladimir Bumbasirevic</name><name sortKey="Janjetovic, Kristina" sort="Janjetovic, Kristina" uniqKey="Janjetovic K" first="Kristina" last="Janjetovic">Kristina Janjetovic</name><name sortKey="Janjetovic, Kristina" sort="Janjetovic, Kristina" uniqKey="Janjetovic K" first="Kristina" last="Janjetovic">Kristina Janjetovic</name><name sortKey="Kravic Stevovic, Tamara" sort="Kravic Stevovic, Tamara" uniqKey="Kravic Stevovic T" first="Tamara" last="Kravic-Stevovic">Tamara Kravic-Stevovic</name><name sortKey="Pantovic, Aleksandar" sort="Pantovic, Aleksandar" uniqKey="Pantovic A" first="Aleksandar" last="Pantovic">Aleksandar Pantovic</name><name sortKey="Petricevic, Sasa" sort="Petricevic, Sasa" uniqKey="Petricevic S" first="Sasa" last="Petricevic">Sasa Petricevic</name><name sortKey="Ristic, Biljana" sort="Ristic, Biljana" uniqKey="Ristic B" first="Biljana" last="Ristic">Biljana Ristic</name><name sortKey="Tovilovic, Gordana" sort="Tovilovic, Gordana" uniqKey="Tovilovic G" first="Gordana" last="Tovilovic">Gordana Tovilovic</name><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name><name sortKey="Zogovic, Nevena" sort="Zogovic, Nevena" uniqKey="Zogovic N" first="Nevena" last="Zogovic">Nevena Zogovic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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