Identification of novel potent and non-toxic anticancer, anti-angiogenic and antimetastatic rhenium complexes against colorectal carcinoma

Joachim Delasoie; Aleksandar Pavic; Noémie Voutier; Sandra Vojnovic; Aurelien Crochet; Jasmina Nikodinovic-Runic; Fabio Zobi

doi:10.1016/j.ejmech.2020.112583

Identification of novel potent and non-toxic anticancer, anti-angiogenic and antimetastatic rhenium complexes against colorectal carcinoma

Eur J Med Chem. 2020 Oct 15:204:112583. doi: 10.1016/j.ejmech.2020.112583. Epub 2020 Jul 12.

Authors

Joachim Delasoie¹, Aleksandar Pavic², Noémie Voutier¹, Sandra Vojnovic³, Aurelien Crochet¹, Jasmina Nikodinovic-Runic⁴, Fabio Zobi⁵

Affiliations

¹ Department of Chemistry, Fribourg University, Chemin Du Musée 9, 1700, Fribourg, Switzerland.
² Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 152, Belgrade, Republic of Serbia. Electronic address: sasapavic@imgge.bg.ac.rs.
³ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 152, Belgrade, Republic of Serbia.
⁴ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 152, Belgrade, Republic of Serbia. Electronic address: jasmina.nikodinovic@imgge.bg.ac.rs.
⁵ Department of Chemistry, Fribourg University, Chemin Du Musée 9, 1700, Fribourg, Switzerland. Electronic address: fabio.zobi@unifr.ch.

PMID: 32731186
DOI: 10.1016/j.ejmech.2020.112583

Abstract

Combination therapy targeting both tumor growth and vascularization is considered to be a cornerstone for colorectal carcinomas (CRC) treatment. However, the major obstacles of most clinical anticancer drugs are their weak selective activity towards cancer cells and inherent inner organs toxicity, accompanied with fast drug resistance development. In our effort to discover novel selective and non-toxic agents effective against CRC, we designed, synthesized and characterized a series of rhenium(I) tricarbonyl-based complexes with increased lipophilicity. Two of these novel compounds were discovered to possess remarkable anticancer, anti-angiogenic and antimetastatic activity in vivo (zebrafish-human HCT-116 xenograft model), being effective at very low doses (1-3 μM). At doses as high as 250 μM the complexes did not provoke toxicity issues encountered in clinical anticancer drugs (cardio-, hepato-, and myelotoxicity). In vivo assays showed that the two compounds exceed the anti-tumor and anti-angiogenic activity of clinical drugs cisplatin and sunitinib malate, and display a large therapeutic window.

Keywords: Angiogenesis; Antimetastatic; Colorectal carcinoma; Rhenium; Xenograft; Zebrafish.

MeSH terms

Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Colorectal Neoplasms / pathology*
Coordination Complexes / chemistry*
Coordination Complexes / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
HCT116 Cells
Humans
Neoplasm Metastasis
Rhenium / chemistry*
Xenograft Model Antitumor Assays
Zebrafish

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Coordination Complexes
Rhenium