Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro
Aim： To investigate the effects of betulinic acid （BA） on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes. Methods： The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytom- etry （FCM）...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2012-12, Vol.33 (12), p.1542-1548 |
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| creator | Yang, Li-jing Chen, Yan He, Jing Yi, Sha Wen, Lu Zhao, Jie Zhang, Ben-ping Cui, Guo-hui |
| description | Aim： To investigate the effects of betulinic acid （BA） on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes. Methods： The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytom- etry （FCM） and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclinl, LC3-11, and P62 were detected using Western blotting. Results： Treatment of KM3 cells with BA （5-25 pg/mL） suppressed the cell proliferation in time- and dose-dependent manners. The IC5o values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 pg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a Specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-11 and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-11 in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-11 in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-11. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis. Conclusion： The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells. |
| doi_str_mv | 10.1038/aps.2012.102 |
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Methods： The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytom- etry （FCM） and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclinl, LC3-11, and P62 were detected using Western blotting. Results： Treatment of KM3 cells with BA （5-25 pg/mL） suppressed the cell proliferation in time- and dose-dependent manners. The IC5o values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 pg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a Specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-11 and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-11 in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-11 in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-11. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis. Conclusion： The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/aps.2012.102</identifier><identifier>PMID: 23064721</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Antineoplastic Agents, Phytogenic - pharmacology ; Antineoplastic Agents, Phytogenic - therapeutic use ; Apoptosis - drug effects ; Autophagy - drug effects ; Biomedical and Life Sciences ; Biomedicine ; Blotting, Western ; Caspase 3 - metabolism ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Humans ; Immunology ; Internal Medicine ; Medical Microbiology ; Multiple Myeloma - drug therapy ; Multiple Myeloma - pathology ; Oligopeptides - pharmacology ; Original ; original-article ; Pharmacology/Toxicology ; Triterpenes - pharmacology ; Triterpenes - therapeutic use ; Vaccine ; 人类 ; 体外诱导 ; 多发性骨髓瘤 ; 桦木 ; 细胞凋亡 ; 自噬 ; 通量 ; 骨髓瘤细胞</subject><ispartof>Acta pharmacologica Sinica, 2012-12, Vol.33 (12), p.1542-1548</ispartof><rights>CPS and SIMM 2012</rights><rights>Copyright Nature Publishing Group Dec 2012</rights><rights>Copyright © 2012 CPS and SIMM 2012 CPS and SIMM</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c542t-28072fee3fd978840c6afdc3be870db5be03bd3c9e28899bc02c13a18abe84f43</citedby><cites>FETCH-LOGICAL-c542t-28072fee3fd978840c6afdc3be870db5be03bd3c9e28899bc02c13a18abe84f43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://image.cqvip.com/vip1000/qk/95561A/95561A.jpg</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001834/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001834/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23064721$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Li-jing</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><creatorcontrib>He, Jing</creatorcontrib><creatorcontrib>Yi, Sha</creatorcontrib><creatorcontrib>Wen, Lu</creatorcontrib><creatorcontrib>Zhao, Jie</creatorcontrib><creatorcontrib>Zhang, Ben-ping</creatorcontrib><creatorcontrib>Cui, Guo-hui</creatorcontrib><title>Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacologica Sinica</addtitle><description>Aim： To investigate the effects of betulinic acid （BA） on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes. Methods： The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytom- etry （FCM） and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclinl, LC3-11, and P62 were detected using Western blotting. Results： Treatment of KM3 cells with BA （5-25 pg/mL） suppressed the cell proliferation in time- and dose-dependent manners. The IC5o values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 pg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a Specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-11 and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-11 in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-11 in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-11. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis. Conclusion： The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells.</description><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Antineoplastic Agents, Phytogenic - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy - drug effects</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blotting, Western</subject><subject>Caspase 3 - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Medical Microbiology</subject><subject>Multiple Myeloma - drug therapy</subject><subject>Multiple Myeloma - pathology</subject><subject>Oligopeptides - pharmacology</subject><subject>Original</subject><subject>original-article</subject><subject>Pharmacology/Toxicology</subject><subject>Triterpenes - pharmacology</subject><subject>Triterpenes - therapeutic 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acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro</title><author>Yang, Li-jing ; Chen, Yan ; He, Jing ; Yi, Sha ; Wen, Lu ; Zhao, Jie ; Zhang, Ben-ping ; Cui, Guo-hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c542t-28072fee3fd978840c6afdc3be870db5be03bd3c9e28899bc02c13a18abe84f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Antineoplastic Agents, Phytogenic - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy - drug effects</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blotting, Western</topic><topic>Caspase 3 - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Immunology</topic><topic>Internal Medicine</topic><topic>Medical Microbiology</topic><topic>Multiple Myeloma - drug therapy</topic><topic>Multiple Myeloma - pathology</topic><topic>Oligopeptides - pharmacology</topic><topic>Original</topic><topic>original-article</topic><topic>Pharmacology/Toxicology</topic><topic>Triterpenes - pharmacology</topic><topic>Triterpenes - therapeutic use</topic><topic>Vaccine</topic><topic>人类</topic><topic>体外诱导</topic><topic>多发性骨髓瘤</topic><topic>桦木</topic><topic>细胞凋亡</topic><topic>自噬</topic><topic>通量</topic><topic>骨髓瘤细胞</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Li-jing</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><creatorcontrib>He, Jing</creatorcontrib><creatorcontrib>Yi, Sha</creatorcontrib><creatorcontrib>Wen, Lu</creatorcontrib><creatorcontrib>Zhao, Jie</creatorcontrib><creatorcontrib>Zhang, Ben-ping</creatorcontrib><creatorcontrib>Cui, 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Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Li-jing</au><au>Chen, Yan</au><au>He, Jing</au><au>Yi, Sha</au><au>Wen, Lu</au><au>Zhao, Jie</au><au>Zhang, Ben-ping</au><au>Cui, Guo-hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacologica Sinica</addtitle><date>2012-12-01</date><risdate>2012</risdate><volume>33</volume><issue>12</issue><spage>1542</spage><epage>1548</epage><pages>1542-1548</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Aim： To investigate the effects of betulinic acid （BA） on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes. Methods： The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytom- etry （FCM） and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclinl, LC3-11, and P62 were detected using Western blotting. Results： Treatment of KM3 cells with BA （5-25 pg/mL） suppressed the cell proliferation in time- and dose-dependent manners. The IC5o values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 pg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a Specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-11 and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-11 in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-11 in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-11. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis. Conclusion： The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23064721</pmid><doi>10.1038/aps.2012.102</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents, Phytogenic - pharmacology Antineoplastic Agents, Phytogenic - therapeutic use Apoptosis - drug effects Autophagy - drug effects Biomedical and Life Sciences Biomedicine Blotting, Western Caspase 3 - metabolism Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Humans Immunology Internal Medicine Medical Microbiology Multiple Myeloma - drug therapy Multiple Myeloma - pathology Oligopeptides - pharmacology Original original-article Pharmacology/Toxicology Triterpenes - pharmacology Triterpenes - therapeutic use Vaccine 人类 体外诱导 多发性骨髓瘤 桦木 细胞凋亡 自噬 通量 骨髓瘤细胞 |
| title | Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro |
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