Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release. (1st December 2018)

• Record Type: Journal Article
• Authors: Mazumder, Aloran; Lee, Jin-Young; Talhi, Oualid; Cerella, Claudia; Chateauvieux, Sébastien; Gaigneaux, Anthoula; Hong, Che Ry; Kang, Hyoung Jin; Lee, Youngjo; Kim, Kyu-Won; Kim, Dong-Wook; Shin, Hee-Young; Dicato, Mario; Bachari, Khaldoun; Silva, Artur M.S.; Orlikova-Boyer, Barbora; Diederich, Marc
• Is Part Of: Cancer letters. Volume 438(2018)
• Page Start: 197
• Page End: 218
• Publication Date: 2018-12-01
• Subjects: Eukaryotic initiation factor 2α -- Calreticulin -- High mobility group box 1 -- Phagocytosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.07.041
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 in vitro and Bcr-Abl + 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. Highlights: OT-55 inhibits cell proliferation and viability in CML. OT-55 induces ER stress, ecto-CRT, ecto-ERp57, ATP and HMGB1 elease leading to immunogenic cell death. OT-55-treated CML cells are phagocytosed by macrophages. OT-55 synergizes with imatinib in CML. OT-55 synergizes with Synribo in Bcr-Abl mutated CML.