Bortezomib Treatment Modulates Autophagy in Multiple Myeloma
Identifieur interne : 000F52 ( Ncbi/Curation ); précédent : 000F51; suivant : 000F53Bortezomib 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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PMC:7073518Le document en format XML
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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>
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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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<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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<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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<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>
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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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<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>
(L.C.);<email>angelo.vacca@uniba.it</email>
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</affiliation>
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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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(A.V.)</nlm:aff>
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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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(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="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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(L.C.);<email>angelo.vacca@uniba.it</email>
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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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(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="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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(N.S.);<email>lucillacrudele@gmail.com</email>
(L.C.);<email>angelo.vacca@uniba.it</email>
(A.V.)</nlm:aff>
</affiliation>
</author>
<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>
(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="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>
</affiliation>
</author>
</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>
</div>
</front>
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