ChloroquineV1, Main, Exploration, bibRecord, 000033

Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia

Identifieur interne : 000033 ( Main/Exploration ); précédent : 000032; suivant : 000034

Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia

Auteurs : Sungmi Song [Corée du Sud] ; Jin-Young Lee [Corée du Sud] ; Ludmila Ermolenko [France] ; Aloran Mazumder [Corée du Sud] ; Seungwon Ji [Corée du Sud] ; Heeju Ryu [Corée du Sud] ; Hyejin Kim [Corée du Sud] ; Dong-Wook Kim [Corée du Sud] ; Jung Weon Lee [Corée du Sud] ; Mario Dicato [Luxembourg (pays)] ; Christo Christov [France] ; Michael Schnekenburger [Luxembourg (pays)] ; Claudia Cerella [Corée du Sud, Luxembourg (pays)] ; Déborah Gérard [Luxembourg (pays)] ; Barbora Orlikova-Boyer [Corée du Sud, Luxembourg (pays)] ; Ali Al-Mourabit [France] ; Marc Diederich [Corée du Sud]

Source :

Cell Death & Disease [ 2041-4889 ] ; 2020.

RBID : PMC:7007439

Abstract

By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential (MMP) and increase of cytosolic free Ca²⁺ levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by N-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box (HMGB1) demonstrating the capacity of this compound to release immunogenic cell death (ICD) markers. We validated the anti-cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007439

DOI: 10.1038/s41419-020-2304-8
PubMed: 32034134
PubMed Central: 7007439

Affiliations:

Le document en format XML

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</placeName>
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</author>
<author><name sortKey="Ryu, Heeju" sort="Ryu, Heeju" uniqKey="Ryu H" first="Heeju" last="Ryu">Heeju Ryu</name>
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<institution-id institution-id-type="GRID">grid.31501.36</institution-id>
<institution>College of Pharmacy,</institution>
<institution>Seoul National University,</institution>
</institution-wrap>
1 Gwanak-ro, Gwanak-gu, Seoul, 08626 Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>1 Gwanak-ro, Gwanak-gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Hyejin" sort="Kim, Hyejin" uniqKey="Kim H" first="Hyejin" last="Kim">Hyejin Kim</name>
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<institution-id institution-id-type="GRID">grid.31501.36</institution-id>
<institution>College of Pharmacy,</institution>
<institution>Seoul National University,</institution>
</institution-wrap>
1 Gwanak-ro, Gwanak-gu, Seoul, 08626 Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>1 Gwanak-ro, Gwanak-gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Dong Wook" sort="Kim, Dong Wook" uniqKey="Kim D" first="Dong-Wook" last="Kim">Dong-Wook Kim</name>
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<institution-id institution-id-type="GRID">grid.411947.e</institution-id>
<institution>Catholic University, Seoul St. Mary’s Hospital,</institution>
</institution-wrap>
Banpo dong 505, Seocho Gu, Seoul, Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Banpo dong 505, Seocho Gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lee, Jung Weon" sort="Lee, Jung Weon" uniqKey="Lee J" first="Jung Weon" last="Lee">Jung Weon Lee</name>
<affiliation wicri:level="3"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0470 5905</institution-id>
<institution-id institution-id-type="GRID">grid.31501.36</institution-id>
<institution>College of Pharmacy,</institution>
<institution>Seoul National University,</institution>
</institution-wrap>
1 Gwanak-ro, Gwanak-gu, Seoul, 08626 Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>1 Gwanak-ro, Gwanak-gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dicato, Mario" sort="Dicato, Mario" uniqKey="Dicato M" first="Mario" last="Dicato">Mario Dicato</name>
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<institution-id institution-id-type="GRID">grid.414194.d</institution-id>
<institution>Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg,</institution>
</institution-wrap>
9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg</nlm:aff>
<country xml:lang="fr">Luxembourg (pays)</country>
<wicri:regionArea>9, rue Edward Steichen, L-2540 Luxembourg</wicri:regionArea>
<wicri:noRegion>L-2540 Luxembourg</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Christov, Christo" sort="Christov, Christo" uniqKey="Christov C" first="Christo" last="Christov">Christo Christov</name>
<affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2194 6418</institution-id>
<institution-id institution-id-type="GRID">grid.29172.3f</institution-id>
<institution>Service d’Histologie, Faculté de Médicine,</institution>
<institution>Université de Lorraine, and INSERM U1256 NGERE,</institution>
</institution-wrap>
54000 Nancy, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>54000 Nancy</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Schnekenburger, Michael" sort="Schnekenburger, Michael" uniqKey="Schnekenburger M" first="Michael" last="Schnekenburger">Michael Schnekenburger</name>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0613 2450</institution-id>
<institution-id institution-id-type="GRID">grid.414194.d</institution-id>
<institution>Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg,</institution>
</institution-wrap>
9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg</nlm:aff>
<country xml:lang="fr">Luxembourg (pays)</country>
<wicri:regionArea>9, rue Edward Steichen, L-2540 Luxembourg</wicri:regionArea>
<wicri:noRegion>L-2540 Luxembourg</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Cerella, Claudia" sort="Cerella, Claudia" uniqKey="Cerella C" first="Claudia" last="Cerella">Claudia Cerella</name>
<affiliation wicri:level="3"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0470 5905</institution-id>
<institution-id institution-id-type="GRID">grid.31501.36</institution-id>
<institution>College of Pharmacy,</institution>
<institution>Seoul National University,</institution>
</institution-wrap>
1 Gwanak-ro, Gwanak-gu, Seoul, 08626 Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>1 Gwanak-ro, Gwanak-gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0613 2450</institution-id>
<institution-id institution-id-type="GRID">grid.414194.d</institution-id>
<institution>Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg,</institution>
</institution-wrap>
9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg</nlm:aff>
<country xml:lang="fr">Luxembourg (pays)</country>
<wicri:regionArea>9, rue Edward Steichen, L-2540 Luxembourg</wicri:regionArea>
<wicri:noRegion>L-2540 Luxembourg</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gerard, Deborah" sort="Gerard, Deborah" uniqKey="Gerard D" first="Déborah" last="Gérard">Déborah Gérard</name>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0613 2450</institution-id>
<institution-id institution-id-type="GRID">grid.414194.d</institution-id>
<institution>Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg,</institution>
</institution-wrap>
9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg</nlm:aff>
<country xml:lang="fr">Luxembourg (pays)</country>
<wicri:regionArea>9, rue Edward Steichen, L-2540 Luxembourg</wicri:regionArea>
<wicri:noRegion>L-2540 Luxembourg</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Orlikova Boyer, Barbora" sort="Orlikova Boyer, Barbora" uniqKey="Orlikova Boyer B" first="Barbora" last="Orlikova-Boyer">Barbora Orlikova-Boyer</name>
<affiliation wicri:level="3"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0470 5905</institution-id>
<institution-id institution-id-type="GRID">grid.31501.36</institution-id>
<institution>College of Pharmacy,</institution>
<institution>Seoul National University,</institution>
</institution-wrap>
1 Gwanak-ro, Gwanak-gu, Seoul, 08626 Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>1 Gwanak-ro, Gwanak-gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0613 2450</institution-id>
<institution-id institution-id-type="GRID">grid.414194.d</institution-id>
<institution>Laboratoire de Biologie Moléculaire du Cancer, Hôpital Kirchberg,</institution>
</institution-wrap>
9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg</nlm:aff>
<country xml:lang="fr">Luxembourg (pays)</country>
<wicri:regionArea>9, rue Edward Steichen, L-2540 Luxembourg</wicri:regionArea>
<wicri:noRegion>L-2540 Luxembourg</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Al Mourabit, Ali" sort="Al Mourabit, Ali" uniqKey="Al Mourabit A" first="Ali" last="Al-Mourabit">Ali Al-Mourabit</name>
<affiliation wicri:level="3"><nlm:aff id="Aff2">Département SNCM (Substances Naturelles et Chimie Médicinale), ICSN-CNRS, LabEx LERMIT, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse (Bat. 27), 91190 Gif-sur-Yvette, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Département SNCM (Substances Naturelles et Chimie Médicinale), ICSN-CNRS, LabEx LERMIT, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse (Bat. 27), 91190 Gif-sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Diederich, Marc" sort="Diederich, Marc" uniqKey="Diederich M" first="Marc" last="Diederich">Marc Diederich</name>
<affiliation wicri:level="3"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0470 5905</institution-id>
<institution-id institution-id-type="GRID">grid.31501.36</institution-id>
<institution>College of Pharmacy,</institution>
<institution>Seoul National University,</institution>
</institution-wrap>
1 Gwanak-ro, Gwanak-gu, Seoul, 08626 Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>1 Gwanak-ro, Gwanak-gu, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death & Disease</title>
<idno type="eISSN">2041-4889</idno>
<imprint><date when="2020">2020</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p id="Par1">By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential (MMP) and increase of cytosolic free Ca<sup>2+</sup>
 levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by <italic>N</italic>
-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box (HMGB1) demonstrating the capacity of this compound to release immunogenic cell death (ICD) markers. We validated the anti-cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models.</p>
</div>
</front>
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Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia

Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia

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Abstract

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