Discovery of a cobalt (III) salen complex that induces apoptosis in Burkitt like lymphoma and leukemia cells, overcoming multidrug resistance in vitro

Sina M Hopff; Liliane A Onambele; Marc Brandenburg; Albrecht Berkessel; Aram Prokop

doi:10.1016/j.bioorg.2020.104193

Discovery of a cobalt (III) salen complex that induces apoptosis in Burkitt like lymphoma and leukemia cells, overcoming multidrug resistance in vitro

Bioorg Chem. 2020 Nov:104:104193. doi: 10.1016/j.bioorg.2020.104193. Epub 2020 Sep 1.

Authors

Sina M Hopff¹, Liliane A Onambele², Marc Brandenburg³, Albrecht Berkessel³, Aram Prokop⁴

Affiliations

¹ Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany. Electronic address: sinamariehopff@t-online.de.
² Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany.
³ Department of Chemistry, Organic Chemistry, University of Cologne, Greinstraße 4, 50939 Cologne, Germany.
⁴ Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamer Straße 59, 50735 Cologne, Germany; Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19055 Schwerin, Germany.

PMID: 32947134
DOI: 10.1016/j.bioorg.2020.104193

Abstract

A very small number of cobalt complexes is examined in oncology research. In this work, we investigate the cobalt (III) salen complex MBR-60 that turns out to be a promising anticancer drug. It induces apoptosis in Nalm6 leukemia and BJAB lymphoma cells and overcomes multidrug resistances by blocking the drug efflux pump P-glycoprotein. It further develops the apoptotic effects over the intrinsic pathway. An activation of caspase-3, caspase-8 and caspase-9 can be detected by western blot analysis. The independence of CD95 is shown by similar apoptotic inductions in BJAB and BJAB FADDdn cells. MBR-60 displays synergistic effects with daunorubicin and vincristine and has a selectivity to tumor cells. In comparison to the apoptotic effects of MBR-60 in BJAB lymphoma cells, the cobalt-free ligand 5 does not influence these cells. The research highlights that a cobalt complex has a therapeutic potential for cancer treating with a focus on drug-resistant tumors.

Keywords: Acute lymphoblastic leukemia; Burkitt like lymphoma; Caspases; Cobalt-salen complex; Multidrug resistance; P-glycoprotein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cobalt / chemistry
Cobalt / pharmacology*
Coordination Complexes / chemical synthesis
Coordination Complexes / chemistry
Coordination Complexes / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Screening Assays, Antitumor
Ethylenediamines / chemistry
Ethylenediamines / pharmacology*
Humans
Mitochondrial Transmembrane Permeability-Driven Necrosis / drug effects
Molecular Structure
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Coordination Complexes
Ethylenediamines
Cobalt
disalicylaldehyde ethylenediamine