Combination Therapy of Chloroquine and C₂-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells.
Identifieur interne : 000060 ( PubMed/Curation ); précédent : 000059; suivant : 000061Combination Therapy of Chloroquine and C₂-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells.
Auteurs : Han-Lin Chou [Taïwan] ; Yi-Hsiung Lin [Taïwan] ; Wangta Liu [Taïwan] ; Chang-Yi Wu [Taïwan] ; Ruei-Nian Li [Taïwan] ; Hurng-Wern Huang [Taïwan] ; Chi-Hsien Chou [Taïwan] ; Shean-Jaw Chiou [Taïwan] ; Chien-Chih Chiu [Taïwan]Source :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
Non-small cell lung cancer (NSCLC) is a type of malignant cancer, and 85% of metastatic NSCLC patients have a poor prognosis. C₂-ceramide induces G2/M phase arrest and cytotoxicity in NSCLC cells. In this study, the autophagy-inducing effect of C₂-ceramide was demonstrated, and cotreatment with the autophagy inhibitor chloroquine (CQ) was investigated in NSCLC H460 and H1299 cells. The results suggested that C₂-ceramide exhibited dose-dependent anticancer effects in H460 and H1299 cells and autophagy induction. Zebrafish-based acridine orange staining confirmed the combined effects in vivo. Importantly, the combination of a sublethal dose of C₂-ceramide and CQ resulted in additive cytotoxicity and autophagy in both cell lines. Alterations of related signaling factors, including Src and SIRT1 inhibition and activation of the autophagic regulators LAMP2 and LC3-I/II, contributed to the autophagy-dependent apoptosis. We found that C₂-ceramide continuously initiated autophagy; however, CQ inhibited autophagosome maturation and degradation during autophagy progression. Accumulated and non-degraded autophagosomes increased NSCLC cell stress, eventually leading to cell death. This study sheds light on improvements to NSCLC chemotherapy to reduce the chemotherapy dose and NSCLC patient burden.
DOI: 10.3390/cancers11030370
PubMed: 30884764
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Medical University, Kaohsiung 807, Taiwan. caminolin@gmail.com.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Wangta" sort="Liu, Wangta" uniqKey="Liu W" first="Wangta" last="Liu">Wangta Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. liuwangta@kmu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author><author><name sortKey="Wu, Chang Yi" sort="Wu, Chang Yi" uniqKey="Wu C" first="Chang-Yi" last="Wu">Chang-Yi Wu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cywu@mail.nsysu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author><author><name sortKey="Li, Ruei Nian" sort="Li, Ruei Nian" uniqKey="Li R" first="Ruei-Nian" last="Li">Ruei-Nian Li</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. runili@kmu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author><author><name sortKey="Huang, Hurng Wern" sort="Huang, Hurng Wern" uniqKey="Huang H" first="Hurng-Wern" last="Huang">Hurng-Wern Huang</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. sting@mail.nsysu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804</wicri:regionArea></affiliation></author><author><name sortKey="Chou, Chi Hsien" sort="Chou, Chi Hsien" uniqKey="Chou C" first="Chi-Hsien" last="Chou">Chi-Hsien Chou</name><affiliation wicri:level="1"><nlm:affiliation>Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan. chishien@kmu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author><author><name sortKey="Chiou, Shean Jaw" sort="Chiou, Shean Jaw" uniqKey="Chiou S" first="Shean-Jaw" last="Chiou">Shean-Jaw Chiou</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. sheanjaw@kmu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author><author><name sortKey="Chiu, Chien Chih" sort="Chiu, Chien Chih" uniqKey="Chiu C" first="Chien-Chih" last="Chiu">Chien-Chih Chiu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cancers</title><idno type="ISSN">2072-6694</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Non-small cell lung cancer (NSCLC) is a type of malignant cancer, and 85% of metastatic NSCLC patients have a poor prognosis. C₂-ceramide induces G2/M phase arrest and cytotoxicity in NSCLC cells. In this study, the autophagy-inducing effect of C₂-ceramide was demonstrated, and cotreatment with the autophagy inhibitor chloroquine (CQ) was investigated in NSCLC H460 and H1299 cells. The results suggested that C₂-ceramide exhibited dose-dependent anticancer effects in H460 and H1299 cells and autophagy induction. Zebrafish-based acridine orange staining confirmed the combined effects in vivo. Importantly, the combination of a sublethal dose of C₂-ceramide and CQ resulted in additive cytotoxicity and autophagy in both cell lines. Alterations of related signaling factors, including Src and SIRT1 inhibition and activation of the autophagic regulators LAMP2 and LC3-I/II, contributed to the autophagy-dependent apoptosis. We found that C₂-ceramide continuously initiated autophagy; however, CQ inhibited autophagosome maturation and degradation during autophagy progression. Accumulated and non-degraded autophagosomes increased NSCLC cell stress, eventually leading to cell death. This study sheds light on improvements to NSCLC chemotherapy to reduce the chemotherapy dose and NSCLC patient burden.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">30884764</PMID><DateRevised><Year>2020</Year><Month>02</Month><Day>25</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Print">2072-6694</ISSN><JournalIssue CitedMedium="Print"><Volume>11</Volume><Issue>3</Issue><PubDate><Year>2019</Year><Month>Mar</Month><Day>15</Day></PubDate></JournalIssue><Title>Cancers</Title><ISOAbbreviation>Cancers (Basel)</ISOAbbreviation></Journal><ArticleTitle>Combination Therapy of Chloroquine and C₂-Ceramide Enhances Cytotoxicity in Lung Cancer H460 and H1299 Cells.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">E370</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.3390/cancers11030370</ELocationID><Abstract><AbstractText>Non-small cell lung cancer (NSCLC) is a type of malignant cancer, and 85% of metastatic NSCLC patients have a poor prognosis. C₂-ceramide induces G2/M phase arrest and cytotoxicity in NSCLC cells. In this study, the autophagy-inducing effect of C₂-ceramide was demonstrated, and cotreatment with the autophagy inhibitor chloroquine (CQ) was investigated in NSCLC H460 and H1299 cells. The results suggested that C₂-ceramide exhibited dose-dependent anticancer effects in H460 and H1299 cells and autophagy induction. Zebrafish-based acridine orange staining confirmed the combined effects in vivo. Importantly, the combination of a sublethal dose of C₂-ceramide and CQ resulted in additive cytotoxicity and autophagy in both cell lines. Alterations of related signaling factors, including Src and SIRT1 inhibition and activation of the autophagic regulators LAMP2 and LC3-I/II, contributed to the autophagy-dependent apoptosis. We found that C₂-ceramide continuously initiated autophagy; however, CQ inhibited autophagosome maturation and degradation during autophagy progression. Accumulated and non-degraded autophagosomes increased NSCLC cell stress, eventually leading to cell death. This study sheds light on improvements to NSCLC chemotherapy to reduce the chemotherapy dose and NSCLC patient burden.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chou</LastName><ForeName>Han-Lin</ForeName><Initials>HL</Initials><AffiliationInfo><Affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. d992050005@gmail.com.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. d992050005@gmail.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lin</LastName><ForeName>Yi-Hsiung</ForeName><Initials>YH</Initials><AffiliationInfo><Affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. caminolin@gmail.com.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. caminolin@gmail.com.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. caminolin@gmail.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Wangta</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. liuwangta@kmu.edu.tw.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Chang-Yi</ForeName><Initials>CY</Initials><AffiliationInfo><Affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cywu@mail.nsysu.edu.tw.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. cywu@mail.nsysu.edu.tw.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Ruei-Nian</ForeName><Initials>RN</Initials><AffiliationInfo><Affiliation>Department of Biomedical Science and Environment Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. runili@kmu.edu.tw.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>Hurng-Wern</ForeName><Initials>HW</Initials><AffiliationInfo><Affiliation>Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. sting@mail.nsysu.edu.tw.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chou</LastName><ForeName>Chi-Hsien</ForeName><Initials>CH</Initials><AffiliationInfo><Affiliation>Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan. chishien@kmu.edu.tw.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chiou</LastName><ForeName>Shean-Jaw</ForeName><Initials>SJ</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. sheanjaw@kmu.edu.tw.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chiu</LastName><ForeName>Chien-Chih</ForeName><Initials>CC</Initials><Identifier Source="ORCID">0000-0001-7307-2468</Identifier><AffiliationInfo><Affiliation>Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. cchiu@kmu.edu.tw.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Research Center for Environment Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Translational Research Center, Cancer Center and Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. cchiu@kmu.edu.tw.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>03</Month><Day>15</Day></ArticleDate></Article><MedlineJournalInfo><Country>Switzerland</Country><MedlineTA>Cancers (Basel)</MedlineTA><NlmUniqueID>101526829</NlmUniqueID><ISSNLinking>2072-6694</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">C2-ceramide</Keyword><Keyword MajorTopicYN="N">NSCLC</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">chloroquine</Keyword><Keyword MajorTopicYN="N">combination treatment</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>11</Month><Day>11</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>02</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>03</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>3</Month><Day>20</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>3</Month><Day>20</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>3</Month><Day>20</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30884764</ArticleId><ArticleId IdType="pii">cancers11030370</ArticleId><ArticleId IdType="doi">10.3390/cancers11030370</ArticleId><ArticleId 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HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Curation/RBID.i -Sk "pubmed:30884764" \
| HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd \
| NlmPubMed2Wicri -a ChloroquineV1
| This area was generated with Dilib version V0.6.33. |  |