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

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.

• Authors: Aloran Mazumder, Jin-Young Lee, Oualid Talhi, Claudia Cerella, Sébastien Chateauvieux, Anthoula Gaigneaux, Che Ry Hong, Hyoung Jin Kang, Youngjo Lee, Kyu-Won Kim, Dong-Wook Kim, Hee-Young Shin, Mario Dicato, Khaldoun Bachari, Artur M S Silva, Barbora Orlikova-Boyer, Marc Diederich
• Journal: Cancer letters (Cancer Lett) Vol. 438 Pg. 197-218 (12 01 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30205168 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Alarmins
• Antineoplastic Agents
• Homoharringtonine
• Imatinib Mesylate

Topics

• Alarmins (metabolism)
• Animals
• Antineoplastic Agents (administration & dosage, chemistry)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Homoharringtonine (administration & dosage)
• Humans
• Imatinib Mesylate (administration & dosage)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, immunology, metabolism)
• Macrophages (immunology)
• Mice
• Phagocytosis (drug effects, immunology)
• Xenograft Model Antitumor Assays (methods)
• Zebrafish