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Lee, Jin-Young,Talhi, Oualid,Jang, Dongman,Cerella, Claudia,Gaigneaux, Anthoula,Kim, Kyu-Won,Lee, Jung Weon,Dicato, Mario,Bachari, Khaldoun,Han, Byung Woo,Silva, Artur M.S.,Orlikova, Barbora,Diederich Elsevier 2018 Cancer letters Vol.416 No.-
<P><B>Abstract</B></P> <P>Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1-targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as <I>in vivo</I> by zebrafish xenografts.</P>
Mazumder, Aloran,Lee, Jin-Young,Talhi, Oualid,Cerella, Claudia,Chateauvieux, Sé,bastien,Gaigneaux, Anthoula,Hong, Che Ry,Kang, Hyoung Jin,Lee, Youngjo,Kim, Kyu-Won,Kim, Dong-Wook,Shin, Hee-Young Elsevier 2018 Cancer letters Vol.438 No.-
<P><B>Abstract</B></P> <P>We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation <I>in vitro</I> and Bcr-Abl<SUP>+</SUP> patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> OT-55 inhibits cell proliferation and viability in CML. </LI> <LI> OT-55 induces ER stress, ecto-CRT, ecto-ERp57, ATP and HMGB1 elease leading to immunogenic cell death. </LI> <LI> OT-55-treated CML cells are phagocytosed by macrophages. </LI> <LI> OT-55 synergizes with imatinib in CML. </LI> <LI> OT-55 synergizes with Synribo in Bcr-Abl mutated CML. </LI> </UL> </P>