SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells
Identifieur interne : 000404 ( Pmc/Checkpoint ); précédent : 000403; suivant : 000405SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells
Auteurs : Jun-Man Hong ; Jin-Hee Kim [Corée du Sud] ; Hyemin Kim [Corée du Sud] ; Wang Jae Lee ; Young-Il HwangSource :
- Molecules [ 1420-3049 ] ; 2019.
Abstract
SB365, a saponin D extracted from the roots of
Url:
DOI: 10.3390/molecules24183230
PubMed: 31491945
PubMed Central: 6766801
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">SB365, <italic>Pulsatilla</italic> Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells</title><author><name sortKey="Hong, Jun Man" sort="Hong, Jun Man" uniqKey="Hong J" first="Jun-Man" last="Hong">Jun-Man Hong</name><affiliation><nlm:aff id="af1-molecules-24-03230">Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</nlm:aff><wicri:noCountry code="subfield">Korea (J.-M.H.) (W.J.L.)</wicri:noCountry></affiliation></author><author><name sortKey="Kim, Jin Hee" sort="Kim, Jin Hee" uniqKey="Kim J" first="Jin-Hee" last="Kim">Jin-Hee Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-03230">Department of Biomedical Laboratory Science, Cheongju University, Cheongju 28503, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biomedical Laboratory Science, Cheongju University, Cheongju 28503</wicri:regionArea><wicri:noRegion>Cheongju 28503</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Hyemin" sort="Kim, Hyemin" uniqKey="Kim H" first="Hyemin" last="Kim">Hyemin Kim</name><affiliation wicri:level="1"><nlm:aff id="af3-molecules-24-03230">Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Wang Jae" sort="Lee, Wang Jae" uniqKey="Lee W" first="Wang Jae" last="Lee">Wang Jae Lee</name><affiliation><nlm:aff id="af1-molecules-24-03230">Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</nlm:aff><wicri:noCountry code="subfield">Korea (J.-M.H.) (W.J.L.)</wicri:noCountry></affiliation></author><author><name sortKey="Hwang, Young Il" sort="Hwang, Young Il" uniqKey="Hwang Y" first="Young-Il" last="Hwang">Young-Il Hwang</name><affiliation><nlm:aff id="af1-molecules-24-03230">Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</nlm:aff><wicri:noCountry code="subfield">Korea (J.-M.H.) (W.J.L.)</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31491945</idno><idno type="pmc">6766801</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766801</idno><idno type="RBID">PMC:6766801</idno><idno type="doi">10.3390/molecules24183230</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000720</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000720</idno><idno type="wicri:Area/Pmc/Curation">000720</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000720</idno><idno type="wicri:Area/Pmc/Checkpoint">000404</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000404</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">SB365, <italic>Pulsatilla</italic> Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells</title><author><name sortKey="Hong, Jun Man" sort="Hong, Jun Man" uniqKey="Hong J" first="Jun-Man" last="Hong">Jun-Man Hong</name><affiliation><nlm:aff id="af1-molecules-24-03230">Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</nlm:aff><wicri:noCountry code="subfield">Korea (J.-M.H.) (W.J.L.)</wicri:noCountry></affiliation></author><author><name sortKey="Kim, Jin Hee" sort="Kim, Jin Hee" uniqKey="Kim J" first="Jin-Hee" last="Kim">Jin-Hee Kim</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-03230">Department of Biomedical Laboratory Science, Cheongju University, Cheongju 28503, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biomedical Laboratory Science, Cheongju University, Cheongju 28503</wicri:regionArea><wicri:noRegion>Cheongju 28503</wicri:noRegion></affiliation></author><author><name sortKey="Kim, Hyemin" sort="Kim, Hyemin" uniqKey="Kim H" first="Hyemin" last="Kim">Hyemin Kim</name><affiliation wicri:level="1"><nlm:aff id="af3-molecules-24-03230">Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Wang Jae" sort="Lee, Wang Jae" uniqKey="Lee W" first="Wang Jae" last="Lee">Wang Jae Lee</name><affiliation><nlm:aff id="af1-molecules-24-03230">Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</nlm:aff><wicri:noCountry code="subfield">Korea (J.-M.H.) (W.J.L.)</wicri:noCountry></affiliation></author><author><name sortKey="Hwang, Young Il" sort="Hwang, Young Il" uniqKey="Hwang Y" first="Young-Il" last="Hwang">Young-Il Hwang</name><affiliation><nlm:aff id="af1-molecules-24-03230">Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</nlm:aff><wicri:noCountry code="subfield">Korea (J.-M.H.) (W.J.L.)</wicri:noCountry></affiliation></author></analytic><series><title level="j">Molecules</title><idno type="eISSN">1420-3049</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>SB365, a saponin D extracted from the roots of <italic>Pulsatilla koreana</italic>, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and <italic>N</italic>-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Morgan, E R" uniqKey="Morgan E">E.R. Morgan</name></author><author><name sortKey="Norman, A" uniqKey="Norman A">A. Norman</name></author><author><name sortKey="Laing, K" uniqKey="Laing K">K. Laing</name></author><author><name sortKey="Seal, M D" uniqKey="Seal M">M.D. Seal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Paolillo, M" uniqKey="Paolillo M">M. Paolillo</name></author><author><name sortKey="Boselli, C" uniqKey="Boselli C">C. Boselli</name></author><author><name sortKey="Schinelli, S" uniqKey="Schinelli S">S. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Molecules</journal-id><journal-id journal-id-type="iso-abbrev">Molecules</journal-id><journal-id journal-id-type="publisher-id">molecules</journal-id><journal-title-group><journal-title>Molecules</journal-title></journal-title-group><issn pub-type="epub">1420-3049</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31491945</article-id><article-id pub-id-type="pmc">6766801</article-id><article-id pub-id-type="doi">10.3390/molecules24183230</article-id><article-id pub-id-type="publisher-id">molecules-24-03230</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>SB365, <italic>Pulsatilla</italic> Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hong</surname><given-names>Jun-Man</given-names></name><xref ref-type="aff" rid="af1-molecules-24-03230">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jin-Hee</given-names></name><xref ref-type="aff" rid="af2-molecules-24-03230">2</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Hyemin</given-names></name><xref ref-type="aff" rid="af3-molecules-24-03230">3</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Wang Jae</given-names></name><xref ref-type="aff" rid="af1-molecules-24-03230">1</xref></contrib><contrib contrib-type="author"><name><surname>Hwang</surname><given-names>Young-il</given-names></name><xref ref-type="aff" rid="af1-molecules-24-03230">1</xref><xref rid="c1-molecules-24-03230" ref-type="corresp">*</xref></contrib></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Fabiani</surname><given-names>Roberto</given-names></name><role>Academic Editor</role></contrib></contrib-group><aff id="af1-molecules-24-03230"><label>1</label>Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea (J.-M.H.) (W.J.L.)</aff><aff id="af2-molecules-24-03230"><label>2</label>Department of Biomedical Laboratory Science, Cheongju University, Cheongju 28503, Korea</aff><aff id="af3-molecules-24-03230"><label>3</label>Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea</aff><author-notes><corresp id="c1-molecules-24-03230"><label>*</label>Correspondence: <email>hyi830@snu.ac.kr</email>; Tel.: +822-740-8209; Fax: +822-745-9528</corresp></author-notes><pub-date pub-type="epub"><day>05</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>9</month><year>2019</year></pub-date><volume>24</volume><issue>18</issue><elocation-id>3230</elocation-id><history><date date-type="received"><day>08</day><month>8</month><year>2019</year></date><date date-type="accepted"><day>04</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>SB365, a saponin D extracted from the roots of <italic>Pulsatilla koreana</italic>, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and <italic>N</italic>-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.</p></abstract><kwd-group><kwd><italic>Pulsatilla</italic> saponin D</kwd><kwd>SB365</kwd><kwd>glioblastoma multiforme</kwd><kwd>temozolomide</kwd><kwd>autophagic flux inhibition</kwd><kwd>lysosomal membrane permeabilization</kwd><kwd>mitochondrial membrane potential</kwd></kwd-group></article-meta></front><floats-group><fig id="molecules-24-03230-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>SB365 exerted a cytotoxic effect on U87-MG cells. (<bold>A</bold>–<bold>C</bold>) SB365 inhibited the proliferation of U87-MG cells. The cells in 96-well plates were treated with SB365 at the indicated concentrations for (<bold>A</bold>) 24, (<bold>B</bold>) 48, or (<bold>C</bold>) 72 h in quadruplicate, and subjected to CCK-8 assay. (<bold>D</bold>,<bold>E</bold>) SB365 increased the frequency of the annexin V-positive cells. U87-MG cells in six-well plates were treated as above, stained with annexin V and 7-AAD, and subjected to FACS analysis. (<bold>D</bold>) A representative FACS profile after 72 h and (<bold>E</bold>) the frequency of annexin V-positive cells. Experiments were performed independently in triplicate. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, and *** <italic>p</italic> < 0.001 vs the control.</p></caption><graphic xlink:href="molecules-24-03230-g001"></graphic></fig><fig id="molecules-24-03230-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>SB365 induced caspase-independent death in U87-MG cells. U87-MG, HT-29 (1 × 10<sup>5</sup>/well), and Huh-7 cells (1 × 10<sup>5</sup>/well) in six-well plates were treated with 10, 5, and 15 μM SB365, respectively. The calculated IC50 values of SB365 on each cell line were 8.9, 5.1, and 13.2 μM, respectively. (<bold>A</bold>) Cell lysates were subjected to western blotting of caspase-3 cleavage, (<bold>B</bold>) followed by densitometry. (<bold>C</bold>) SB365 induced nuclear fragmentation in HT-29 and Huh-7 cells, but not in U87-MG cells. Cells were treated with 10 μM SB365 for 72 h, adhered to an eight-well multispot slide, and stained with DAPI (blue). Arrows indicate fragmented nuclei. Images were acquired using a fluorescence microscope (x 400). The scale bar represents 50 μm. CTL, control group; SB, SB365-treated group.</p></caption><graphic xlink:href="molecules-24-03230-g002"></graphic></fig><fig id="molecules-24-03230-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>SB365 inhibited autophagic flux in U87-MG cells. Western blot analysis of autophagy-related proteins within 24 h of treatment with SB365. U87-MG cells in a six-well plate were treated with 10 μM SB365 for the indicated times. (<bold>A</bold>) Cell lysates were subjected to western blotting for LC3-I, II, beclin-1, and <italic>p</italic>62, and (<bold>B</bold>) the LC3-II/I, beclin-1/β-actin, and <italic>p</italic>62/β-actin ratios were calculated. The experiment was performed independently in triplicate. * <italic>p</italic> < 0.05 vs the control.</p></caption><graphic xlink:href="molecules-24-03230-g003"></graphic></fig><fig id="molecules-24-03230-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>SB365 deteriorated lysosomal stability and mitochondrial membrane potential (MMP) in U87-MG cells. (<bold>A</bold>) SB365 induced lysosomal pH neutralization in U87-MG cells. Cells were treated with 10 μM SB365 for the indicated times, stained with (<bold>A</bold>) 3 μg/mL acridine orange for lysosomal stability measurement. (<bold>B</bold>) SB365 induced mitochondrial depolarization in U87-MG cells. Cells were stained with 2.5 μM JC-1 for 20 min for MMP measurement, harvested, and analyzed by flow cytometry. Cells treated with 0.5 mM H<sub>2</sub>O<sub>2</sub> for 2 h constituted the positive control. (<bold>C</bold>) Combination of (<bold>A</bold>) and (<bold>B</bold>). The experiment was performed independently in triplicate.</p></caption><graphic xlink:href="molecules-24-03230-g004"></graphic></fig><fig id="molecules-24-03230-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>SB365 induced cell death via cathepsin B and ROS in U87-MG cells. (<bold>A</bold>) A cathepsin B inhibitor partially restored inhibited proliferation of U87-MG cells induced by SB365. Cells were cultured in 96-well plates, treated with 10 μM SB365 for 72 h in the presence of the indicated concentrations of cathepsin B inhibitor, and subjected to CCK-8 assay. (<bold>B</bold>) A cathepsin B inhibitor partially recovered SB365 induced MMP deterioration. U87-MG cells were treated with 10 μM SB365 for 72 h in the presence of 5 μM cathepsin B inhibitor, stained with JC-1, and MMP was analyzed by FACS. (<bold>C</bold>) NAC partially reduced the anti-proliferative effect of SB365 in U87-MG cells. Cells were cultured in 96-well plates, treated with 10 μM SB365 for 72 h in the presence of the indicated concentrations of NAC, and subjected to CCK-8 assay. NAC was added to the culture medium 1 h after SB365 treatment. (<bold>D)</bold> The same experiments were performed as in (<bold>C</bold>) with 2.5 mM NAC. However, NAC was treated 24 and 48 h after SB365 treatment, in addition to 1 h treatment. Quadruplicate samples were analyzed independently in triplicate. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001 vs the control; # <italic>p</italic> < 0.05, ## <italic>p</italic> < 0.01, and ### <italic>p</italic> < 0.001 vs the SB365 group. CTSB, cathepsin B; NAC, <italic>N</italic>-acetyl cysteine.</p></caption><graphic xlink:href="molecules-24-03230-g005"></graphic></fig><fig id="molecules-24-03230-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>SB365 augmented the cytotoxic effect of TMZ on U87-MG cells. Cells were cultured in 96-well plates, treated with the indicated concentrations of TMZ in the (<bold>A</bold>) absence or (<bold>B</bold>) presence of 10 μM SB365, and subjected to CCK-8 assay. Quadruplicate samples were analyzed independently in triplicate. ** <italic>p</italic> < 0.01, and *** <italic>p</italic> < 0.001 vs the control; # <italic>p</italic> < 0.05, ## <italic>p</italic> < 0.01, and ### <italic>p</italic> < 0.001 vs the SB365 group. CTL, control; TMZ, temozolomide.</p></caption><graphic xlink:href="molecules-24-03230-g006"></graphic></fig><fig id="molecules-24-03230-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Combination of SB365 with TMZ additively suppressed the growth of U87-MG tumors in a mouse xenograft model. U87-MG cells were subcutaneously inoculated into both flanks of nude mice. When the tumor reached a volume of ~100–200 mm<sup>3</sup>, mice were intratumorally administered with SB365 every other day and/or with TMZ intraperitoneally daily for 22 days. The control received vehicle (<3% DMSO). (<bold>A</bold>) Body weight and (<bold>B</bold>) tumor size were measured every other day. The mice were euthanized, and (<bold>C</bold>) the tumors were extracted and (<bold>D</bold>) weighed. <italic>n</italic> = 8 per group. * <italic>p</italic> < 0.05 and ** <italic>p</italic> < 0.01 vs the control. SB365, SB365-treated group; TMZ, temozolomide-treated group.</p></caption><graphic xlink:href="molecules-24-03230-g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Corée du Sud</li></country><region><li>Région capitale de Séoul</li></region><settlement><li>Séoul</li></settlement></list><tree><noCountry><name sortKey="Hong, Jun Man" sort="Hong, Jun Man" uniqKey="Hong J" first="Jun-Man" last="Hong">Jun-Man Hong</name><name sortKey="Hwang, Young Il" sort="Hwang, Young Il" uniqKey="Hwang Y" first="Young-Il" last="Hwang">Young-Il Hwang</name><name sortKey="Lee, Wang Jae" sort="Lee, Wang Jae" uniqKey="Lee W" first="Wang Jae" last="Lee">Wang Jae Lee</name></noCountry><country name="Corée du Sud"><noRegion><name sortKey="Kim, Jin Hee" sort="Kim, Jin Hee" uniqKey="Kim J" first="Jin-Hee" last="Kim">Jin-Hee Kim</name></noRegion><name sortKey="Kim, Hyemin" sort="Kim, Hyemin" uniqKey="Kim H" first="Hyemin" last="Kim">Hyemin Kim</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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