Bortezomib Treatment Modulates Autophagy in Multiple Myeloma
Identifieur interne : 000670 ( Pmc/Curation ); précédent : 000669; suivant : 000671Bortezomib Treatment Modulates Autophagy in Multiple Myeloma
Auteurs : Giuseppe Di Lernia ; Patrizia Leone ; Antonio Giovanni Solimando ; Alessio Buonavoglia ; Ilaria Saltarella ; Roberto Ria ; Paolo Ditonno ; Nicola Silvestris ; Lucilla Crudele ; Angelo Vacca ; Vito RacanelliSource :
- Journal of Clinical Medicine [ 2077-0383 ] ; 2020.
Abstract
Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.
Url:
DOI: 10.3390/jcm9020552
PubMed: 32085480
PubMed Central: 7073518
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<author><name sortKey="Di Lernia, Giuseppe" sort="Di Lernia, Giuseppe" uniqKey="Di Lernia G" first="Giuseppe" last="Di Lernia">Giuseppe Di Lernia</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
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<author><name sortKey="Leone, Patrizia" sort="Leone, Patrizia" uniqKey="Leone P" first="Patrizia" last="Leone">Patrizia Leone</name>
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<author><name sortKey="Solimando, Antonio Giovanni" sort="Solimando, Antonio Giovanni" uniqKey="Solimando A" first="Antonio Giovanni" last="Solimando">Antonio Giovanni Solimando</name>
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<affiliation><nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;<email>paolo.ditonno@fastwebnet.it</email>
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<author><name sortKey="Buonavoglia, Alessio" sort="Buonavoglia, Alessio" uniqKey="Buonavoglia A" first="Alessio" last="Buonavoglia">Alessio Buonavoglia</name>
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<author><name sortKey="Saltarella, Ilaria" sort="Saltarella, Ilaria" uniqKey="Saltarella I" first="Ilaria" last="Saltarella">Ilaria Saltarella</name>
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<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
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<author><name sortKey="Ditonno, Paolo" sort="Ditonno, Paolo" uniqKey="Ditonno P" first="Paolo" last="Ditonno">Paolo Ditonno</name>
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<author><name sortKey="Silvestris, Nicola" sort="Silvestris, Nicola" uniqKey="Silvestris N" first="Nicola" last="Silvestris">Nicola Silvestris</name>
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</nlm:aff>
</affiliation>
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<author><name sortKey="Crudele, Lucilla" sort="Crudele, Lucilla" uniqKey="Crudele L" first="Lucilla" last="Crudele">Lucilla Crudele</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
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<author><name sortKey="Vacca, Angelo" sort="Vacca, Angelo" uniqKey="Vacca A" first="Angelo" last="Vacca">Angelo Vacca</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
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<author><name sortKey="Racanelli, Vito" sort="Racanelli, Vito" uniqKey="Racanelli V" first="Vito" last="Racanelli">Vito Racanelli</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Bortezomib Treatment Modulates Autophagy in Multiple Myeloma</title>
<author><name sortKey="Di Lernia, Giuseppe" sort="Di Lernia, Giuseppe" uniqKey="Di Lernia G" first="Giuseppe" last="Di Lernia">Giuseppe Di Lernia</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
(P.L.);<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);<email>ilaria.saltarella@libero.it</email>
(I.S.);<email>roberto.ria@uniba.it</email>
(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
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<author><name sortKey="Leone, Patrizia" sort="Leone, Patrizia" uniqKey="Leone P" first="Patrizia" last="Leone">Patrizia Leone</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
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(I.S.);<email>roberto.ria@uniba.it</email>
(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
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<author><name sortKey="Solimando, Antonio Giovanni" sort="Solimando, Antonio Giovanni" uniqKey="Solimando A" first="Antonio Giovanni" last="Solimando">Antonio Giovanni Solimando</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
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(A.V.)</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;<email>paolo.ditonno@fastwebnet.it</email>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Buonavoglia, Alessio" sort="Buonavoglia, Alessio" uniqKey="Buonavoglia A" first="Alessio" last="Buonavoglia">Alessio Buonavoglia</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
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(A.V.)</nlm:aff>
</affiliation>
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<author><name sortKey="Saltarella, Ilaria" sort="Saltarella, Ilaria" uniqKey="Saltarella I" first="Ilaria" last="Saltarella">Ilaria Saltarella</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
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(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
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<author><name sortKey="Ria, Roberto" sort="Ria, Roberto" uniqKey="Ria R" first="Roberto" last="Ria">Roberto Ria</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
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<author><name sortKey="Ditonno, Paolo" sort="Ditonno, Paolo" uniqKey="Ditonno P" first="Paolo" last="Ditonno">Paolo Ditonno</name>
<affiliation><nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;<email>paolo.ditonno@fastwebnet.it</email>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Silvestris, Nicola" sort="Silvestris, Nicola" uniqKey="Silvestris N" first="Nicola" last="Silvestris">Nicola Silvestris</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
(P.L.);<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);<email>ilaria.saltarella@libero.it</email>
(I.S.);<email>roberto.ria@uniba.it</email>
(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="af2-jcm-09-00552">IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;<email>paolo.ditonno@fastwebnet.it</email>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Crudele, Lucilla" sort="Crudele, Lucilla" uniqKey="Crudele L" first="Lucilla" last="Crudele">Lucilla Crudele</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
(P.L.);<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);<email>ilaria.saltarella@libero.it</email>
(I.S.);<email>roberto.ria@uniba.it</email>
(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vacca, Angelo" sort="Vacca, Angelo" uniqKey="Vacca A" first="Angelo" last="Vacca">Angelo Vacca</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
(P.L.);<email>antoniogiovannisolimando@gmail.com</email>
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(A.B.);<email>ilaria.saltarella@libero.it</email>
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(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Racanelli, Vito" sort="Racanelli, Vito" uniqKey="Racanelli V" first="Vito" last="Racanelli">Vito Racanelli</name>
<affiliation><nlm:aff id="af1-jcm-09-00552">Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
(P.L.);<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);<email>ilaria.saltarella@libero.it</email>
(I.S.);<email>roberto.ria@uniba.it</email>
(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
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</analytic>
<series><title level="j">Journal of Clinical Medicine</title>
<idno type="eISSN">2077-0383</idno>
<imprint><date when="2020">2020</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p>Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.</p>
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</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Med</journal-id>
<journal-id journal-id-type="iso-abbrev">J Clin Med</journal-id>
<journal-id journal-id-type="publisher-id">jcm</journal-id>
<journal-title-group><journal-title>Journal of Clinical Medicine</journal-title>
</journal-title-group>
<issn pub-type="epub">2077-0383</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32085480</article-id>
<article-id pub-id-type="pmc">7073518</article-id>
<article-id pub-id-type="doi">10.3390/jcm9020552</article-id>
<article-id pub-id-type="publisher-id">jcm-09-00552</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Bortezomib Treatment Modulates Autophagy in Multiple Myeloma</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8181-5986</contrib-id>
<name><surname>Di Lernia</surname>
<given-names>Giuseppe</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="author-notes" rid="fn1-jcm-09-00552">†</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0904-1074</contrib-id>
<name><surname>Leone</surname>
<given-names>Patrizia</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="author-notes" rid="fn1-jcm-09-00552">†</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2293-9698</contrib-id>
<name><surname>Solimando</surname>
<given-names>Antonio Giovanni</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="aff" rid="af2-jcm-09-00552">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Buonavoglia</surname>
<given-names>Alessio</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saltarella</surname>
<given-names>Ilaria</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-1515-0090</contrib-id>
<name><surname>Ria</surname>
<given-names>Roberto</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ditonno</surname>
<given-names>Paolo</given-names>
</name>
<xref ref-type="aff" rid="af2-jcm-09-00552">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7814-7318</contrib-id>
<name><surname>Silvestris</surname>
<given-names>Nicola</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref ref-type="aff" rid="af2-jcm-09-00552">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Crudele</surname>
<given-names>Lucilla</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4567-8216</contrib-id>
<name><surname>Vacca</surname>
<given-names>Angelo</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8639-1940</contrib-id>
<name><surname>Racanelli</surname>
<given-names>Vito</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-09-00552">1</xref>
<xref rid="c1-jcm-09-00552" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-jcm-09-00552"><label>1</label>
Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine “Guido Baccelli”, University of Bari Medical School, 70124 Bari, Italy;<email>giuseppe.dilernia@uniba.it</email>
(G.D.L.);<email>patrizia.leone@uniba.it</email>
(P.L.);<email>antoniogiovannisolimando@gmail.com</email>
(A.G.S.);<email>alessio.buonavoglia85@gmail.com</email>
(A.B.);<email>ilaria.saltarella@libero.it</email>
(I.S.);<email>roberto.ria@uniba.it</email>
(R.R.);<email>n.silvestris@oncologico.bari.it</email>
(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</aff>
<aff id="af2-jcm-09-00552"><label>2</label>
IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;<email>paolo.ditonno@fastwebnet.it</email>
</aff>
<author-notes><corresp id="c1-jcm-09-00552"><label>*</label>
Correspondence: <email>vito.racanelli1@uniba.it</email>
</corresp>
<fn id="fn1-jcm-09-00552"><label>†</label>
<p>Giuseppe Di Lernia and Patrizia Leone contributed equally to this work and should be considered co-first authors.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>18</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><month>2</month>
<year>2020</year>
</pub-date>
<volume>9</volume>
<issue>2</issue>
<elocation-id>552</elocation-id>
<history><date date-type="received"><day>16</day>
<month>1</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>13</day>
<month>2</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© 2020 by the authors.</copyright-statement>
<copyright-year>2020</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>Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.</p>
</abstract>
<kwd-group><kwd>autophagy</kwd>
<kwd>angiogenesis</kwd>
<kwd>multiple myeloma</kwd>
<kwd>plasma cells</kwd>
<kwd>endothelial cells</kwd>
<kwd>drug resistance</kwd>
<kwd>bortezomib</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="jcm-09-00552-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Schematic overview of the experimental design. Cytoplasmic cargo material including mitochondria, membrane, and unfolded proteins is engulfed by a double-membrane vesicle to form and elongate into an autophagosome. Autophagy related (ATG) proteins create two “ubiquitin-like conjugation systems” that catalyze the conversion of LC3B-I to its phosphatidylethanolamine (PE)-conjugated LC3B-II form. LC3B-II protein is recruited to the autophagosome and P62 along with the attached ubiquitinated proteins bind to LC3B-II protein. The complex LC3B-II-p62 is then incorporated into the autophagosome membrane, where it serves as a docking site of adaptor proteins and bound cargo. The mature autophagosome then fuses with the lysosome and forms an autolysosome, leading to cargo degradation and recycling of nutrients and metabolites. Hydroxychloroquine inhibits autophagosome–lysosome fusion and degradation. Thus, HCQ treatment promotes intracellular autophagosome accumulation that correlates with LC3B-II and p62 levels.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g001"></graphic>
</fig>
<fig id="jcm-09-00552-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Bortezomib and hydroxychloroquine combination decreases autophagosome formation acting as a downregulator of autophagic flux in plasma cells (PCs). RPMI 8226 (<bold>A</bold>
) and JJN-3 (<bold>D</bold>
) cells were treated with or without bortezomib (10 nM), hydroxychloroquine (HCQ, 100 uM), or with both drugs for 24 h, followed by immunoblotting analysis to determine LC3B-II and p62 expression levels under each condition. Densitometric analysis of RPMI 8226 (<bold>B</bold>
,<bold>C</bold>
) and JJN-3 (<bold>E</bold>
,<bold>F</bold>
) lysates for LC3B-II (<bold>B</bold>
,<bold>E</bold>
) and p62 (<bold>C</bold>
,<bold>F</bold>
) expression. The results are expressed as fold-change normalized to the β-actin level and relative to the control. Mann–Whitney U test.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g002"></graphic>
</fig>
<fig id="jcm-09-00552-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Bortezomib and hydroxychloroquine combination downregulates the autophagic flux in plasma cells (PCs). Changes in LC3B-II and p62 levels upon treatment with hydroxychloroquine (HCQ, 100 uM) alone or both bortezomib (10 nM) and HCQ for 24 h, determined by flow cytometry. Mean Fluorescence intensity (<bold>A</bold>
,<bold>C</bold>
) and representative plots (<bold>B</bold>
,<bold>D</bold>
) of primary plasma cells isolated from MM patients (<italic>n</italic>
= 6). Mann–Whitney U test.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g003"></graphic>
</fig>
<fig id="jcm-09-00552-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Bortezomib and hydroxychloroquine combination upregulates autophagosome formation in endothelial cells (ECs). (<bold>A</bold>
) Human umbilical vein endothelial cells (HUVECs), (<bold>D</bold>
) ECs from monoclonal gammopathy of undetermined significance (MGECs, <italic>n</italic>
= 9) and ECs from multiple myeloma (MMECs, <italic>n</italic>
= 11) were treated with or without bortezomib (10 nM), HCQ (100 uM), or with both drugs for 24 h, followed by immunoblotting to determine LC3B-II and p62 levels under each condition. (<bold>B</bold>
–<bold>F</bold>
) Densitometric analysis of HUVEC (<bold>B</bold>
,<bold>C</bold>
), MGEC (black bars), and MMEC (gray bars) (<bold>E</bold>
,<bold>F</bold>
) lysates for LC3B-II (<bold>B</bold>
,<bold>E</bold>
) and p62 (<bold>C</bold>
,<bold>F</bold>
) expression. The results are expressed as fold-change normalized to the β-actin level and relative to the control. Mann–Whitney U test.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g004"></graphic>
</fig>
<fig id="jcm-09-00552-f005" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>Bortezomib and hydroxychloroquine combination increases autophagosome number in ECs. (<bold>A</bold>
) HUVECs, MGECs (<italic>n</italic>
= 4), and MMECs (<italic>n</italic>
= 4) were treated with HCQ (100 uM), bortezomib (10 nM), or both drugs. Representative photomicrographs (on the left) and flow cytometry plots (on the right) of four independent experiments are shown. Black arrows indicate autophagosome vacuoles (magnification 20×).</p>
</caption>
<graphic xlink:href="jcm-09-00552-g005"></graphic>
</fig>
<fig id="jcm-09-00552-f006" orientation="portrait" position="float"><label>Figure 6</label>
<caption><p>Bortezomib and HCQ differentially modulate MM cell proliferation. RPMI 8226 cells (<bold>A</bold>
), MGECs (<italic>n</italic>
= 6) (<bold>B</bold>
), and MMECs (<italic>n</italic>
= 6) (<bold>C</bold>
) were treated with or without bortezomib (10 nM), HCQ (100 uM) or with both drugs for 24 h, after which the inhibition of proliferation was evaluated by measuring cell viability. Mann–Whitney U test. ns = not significant.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g006"></graphic>
</fig>
<fig id="jcm-09-00552-f007" orientation="portrait" position="float"><label>Figure 7</label>
<caption><p>Effect of combination treatment with bortezomib and HCQ on cell cytotoxicity. Representative flow cytometry plots show changes in cytotoxicity for (<bold>A</bold>
) RPMI 8226 cells, (<bold>B</bold>
) MGECs (<italic>n</italic>
= 9), and (<bold>C</bold>
) MMECs (<italic>n</italic>
= 11) treated with or without bortezomib (10 nM), HCQ (100 uM), or with both drugs for 24 h.</p>
</caption>
<graphic xlink:href="jcm-09-00552-g007"></graphic>
</fig>
<table-wrap id="jcm-09-00552-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">jcm-09-00552-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>Abbreviations and acronyms.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Abbreviation</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Full Form and Definition</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">MM</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Multiple myeloma</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MGUS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Monoclonal gammopathy of undetermined significance</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">PCs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Plasma cells</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">HCQ</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Hydroxychloroquine</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">ECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endothelial cells</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MGECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endothelial cells from MGUS patients</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MMECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endothelial cells from MM patients</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">BMMCs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Bone marrow mononuclear cells</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">ATG</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Autophagy related</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MAP1LC3A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Microtubule-associated proteins 1A/1B light chain 3A</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MAP1LC3B</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Microtubule-associated proteins 1A/1B light chain 3B or LC3</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">LC3B</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Microtubule-associated protein light chain beta</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">LC3-I</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cytosolic form of LC3</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">LC3-II</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Membrane-bound form of LC3, phosphatidylethanolamine conjugated</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">RPMI 8226</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human myeloma cell line</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">JJN3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human myeloma cell line</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">HUVECs</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human umbilical vein endothelial cells</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">ER</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Endoplasmic reticulum</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">PKR-like</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Protein kinase R-like</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">STRING</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Biological database and web resource of known and predicted protein–protein interactions</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">SQSTM-1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Sequestosome-1 also known as p62</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">KRAS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Kirsten rat sarcoma viral oncogene homolog</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MAF1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Repressor of RNA polymerase III transcription</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">CDKN2A</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Cyclin-dependent kinase Inhibitor 2A</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">TP53</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Tumoral protein 53</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">BCL2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">B-cell lymphoma 2. Apoptosis regulator</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">MYC</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Family of regulator genes and proto-oncogenes that code for transcription factors</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">EGFR2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Epidermal growth factor receptor 2</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">ERBB2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Erythroblastic oncogene B2. Receptor tyrosine kinase</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RAF-1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Proto-oncogene, serine/threonine kinase</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
</record>
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