Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release

• Published in: Cancer letters 2018-12, Vol.438, p.197-218
• Main 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
• Format: Article
• Language: English
• Subjects: Animal models; Antibiotics; Apoptosis; BCR-ABL protein; Calreticulin; Cancer therapies; Caspase; Cell activation; Cell culture; Chronic myeloid leukemia; Danio rerio; Eukaryotic initiation factor 2α; Fusion protein; High mobility group box 1; Hydrogen bonds; Imatinib; Inhibitor drugs; Leukemia; Macrophages; Mcl-1 protein; Monocytes; Myeloid leukemia; Partnership agreements; Phagocytosis; Synergistic effect; Targeted cancer therapy; Toxicity; Tumor necrosis factor-α; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.07.041

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. •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.