Targeting heme Oxygenase-1 with hybrid compounds to overcome Imatinib resistance in chronic myeloid leukemia cell lines

Valeria Sorrenti; Valeria Pittalà; Giuseppe Romeo; Emanuele Amata; Maria Dichiara; Agostino Marrazzo; Rita Turnaturi; Orazio Prezzavento; Ignazio Barbagallo; Luca Vanella; Antonio Rescifina; Giuseppe Floresta; Daniele Tibullo; Francesco Di Raimondo; Sebastiano Intagliata; Loredana Salerno

doi:10.1016/j.ejmech.2018.09.048

Targeting heme Oxygenase-1 with hybrid compounds to overcome Imatinib resistance in chronic myeloid leukemia cell lines

Eur J Med Chem. 2018 Oct 5:158:937-950. doi: 10.1016/j.ejmech.2018.09.048. Epub 2018 Sep 17.

Authors

Valeria Sorrenti¹, Valeria Pittalà², Giuseppe Romeo¹, Emanuele Amata¹, Maria Dichiara¹, Agostino Marrazzo¹, Rita Turnaturi¹, Orazio Prezzavento¹, Ignazio Barbagallo¹, Luca Vanella¹, Antonio Rescifina¹, Giuseppe Floresta³, Daniele Tibullo⁴, Francesco Di Raimondo⁵, Sebastiano Intagliata⁶, Loredana Salerno⁷

Affiliations

¹ Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125, Catania, Italy.
² Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125, Catania, Italy. Electronic address: vpittala@unict.it.
³ Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125, Catania, Italy; Department of Chemical Sciences, University of Catania, viale A. Doria 6, 95125, Catania, Italy.
⁴ Division of Hematology, A.O.U. Policlinico-OVE, University of Catania, via S. Sofia, 78, 95123, Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 78, 95123, Catania, Italy.
⁵ Division of Hematology, A.O.U. Policlinico-OVE, University of Catania, via S. Sofia, 78, 95123, Catania, Italy.
⁶ Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
⁷ Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125, Catania, Italy. Electronic address: l.salerno@unict.it.

PMID: 30261468
DOI: 10.1016/j.ejmech.2018.09.048

Abstract

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme and a survival-enhancing factor in a number of cancers. Chronic myeloid leukemia (CML) is a blood cancer caused by pathological kinase activity of the BCR-ABL protein, currently treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM). However, resistance to TKIs persists in a number of patients and HO-1 overexpression has been linked with the induction of chemoresistance in CML. With this in mind, in this study, we designed and synthesized the first series of hybrid compounds obtained by combining the structures of IM, as BCR-ABL inhibitor, with imidazole-based HO-1 inhibitors. We found that many hybrids were able to inhibit the enzymatic activity of both targets and to reduce the viability of CML-IM resistant cells, showing that a single molecular entity may reduce the resistance phenomenon.

Keywords: BCR-ABL; Chronic myeloid leukemia; HO-1 inhibitors; Imatinib; Tyrosine kinase inhibitors.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Survival / drug effects
Drug Design
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl / antagonists & inhibitors
Fusion Proteins, bcr-abl / metabolism
Heme Oxygenase-1 / antagonists & inhibitors*
Heme Oxygenase-1 / metabolism
Humans
Imatinib Mesylate / analogs & derivatives*
Imatinib Mesylate / chemical synthesis
Imatinib Mesylate / pharmacology*
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology*
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
Molecular Docking Simulation

Substances

Antineoplastic Agents
Imidazoles
Imatinib Mesylate
Heme Oxygenase-1
Fusion Proteins, bcr-abl