Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells.
Identifieur interne : 000E90 ( Main/Exploration ); précédent : 000E89; suivant : 000E91Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells.
Auteurs : Lars Ulrik Nordstr M [États-Unis] ; Juan Sironi [États-Unis] ; Evelyn Aranda [États-Unis] ; Jorge Maisonet [États-Unis] ; Roman Perez-Soler [États-Unis] ; Peng Wu [États-Unis] ; Edward L. Schwartz [États-Unis]Source :
- ACS medicinal chemistry letters [ 1948-5875 ] ; 2015.
Abstract
The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines; however, low potency may limit their antitumor efficacy clinically. We synthesized a series of chloroquine analogs that retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460 and HCC827 human lung cancer and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had an IC50 of 5.8 μM in the BxPC3 cells and was approximately 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62 and induced apoptosis. The increases in LC3-II levels by the analogues were highly correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. EAD1 is a viable lead compound for evaluation of the antitumor activity of autophagy inhibitors in vivo.
DOI: 10.1021/ml500348p
PubMed: 25699157
Affiliations:
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Medicine , Bronx, New York 10461, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461</wicri:regionArea><wicri:noRegion>New York 10461</wicri:noRegion></affiliation></author><author><name sortKey="Sironi, Juan" sort="Sironi, Juan" uniqKey="Sironi J" first="Juan" last="Sironi">Juan Sironi</name><affiliation wicri:level="1"><nlm:affiliation>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461</wicri:regionArea><wicri:noRegion>New York 10461</wicri:noRegion></affiliation></author><author><name sortKey="Aranda, Evelyn" sort="Aranda, Evelyn" uniqKey="Aranda E" first="Evelyn" last="Aranda">Evelyn Aranda</name><affiliation wicri:level="1"><nlm:affiliation>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461</wicri:regionArea><wicri:noRegion>New York 10461</wicri:noRegion></affiliation></author><author><name sortKey="Maisonet, Jorge" sort="Maisonet, Jorge" uniqKey="Maisonet J" first="Jorge" last="Maisonet">Jorge Maisonet</name><affiliation wicri:level="1"><nlm:affiliation>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 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xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461</wicri:regionArea><wicri:noRegion>New York 10461</wicri:noRegion></affiliation></author><author><name sortKey="Schwartz, Edward L" sort="Schwartz, Edward L" uniqKey="Schwartz E" first="Edward L" last="Schwartz">Edward L. Schwartz</name><affiliation wicri:level="1"><nlm:affiliation>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461</wicri:regionArea><wicri:noRegion>New York 10461</wicri:noRegion></affiliation></author></analytic><series><title level="j">ACS medicinal chemistry letters</title><idno type="ISSN">1948-5875</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines; however, low potency may limit their antitumor efficacy clinically. We synthesized a series of chloroquine analogs that retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460 and HCC827 human lung cancer and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had an IC50 of 5.8 μM in the BxPC3 cells and was approximately 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62 and induced apoptosis. The increases in LC3-II levels by the analogues were highly correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. EAD1 is a viable lead compound for evaluation of the antitumor activity of autophagy inhibitors in vivo. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Nordstr M, Lars Ulrik" sort="Nordstr M, Lars Ulrik" uniqKey="Nordstr M L" first="Lars Ulrik" last="Nordstr M">Lars Ulrik Nordstr M</name></noRegion><name sortKey="Aranda, Evelyn" sort="Aranda, Evelyn" uniqKey="Aranda E" first="Evelyn" last="Aranda">Evelyn Aranda</name><name sortKey="Maisonet, Jorge" sort="Maisonet, Jorge" uniqKey="Maisonet J" first="Jorge" last="Maisonet">Jorge Maisonet</name><name sortKey="Perez Soler, Roman" sort="Perez Soler, Roman" uniqKey="Perez Soler R" first="Roman" last="Perez-Soler">Roman Perez-Soler</name><name sortKey="Schwartz, Edward L" sort="Schwartz, Edward L" uniqKey="Schwartz E" first="Edward L" last="Schwartz">Edward L. Schwartz</name><name sortKey="Sironi, Juan" sort="Sironi, Juan" uniqKey="Sironi J" first="Juan" last="Sironi">Juan Sironi</name><name sortKey="Wu, Peng" sort="Wu, Peng" uniqKey="Wu P" first="Peng" last="Wu">Peng Wu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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