Copper transporter 1 affinity as a delivery strategy to improve the cytotoxic profile of rationally designed copper(II) complexes for cancer treatment

Author(s)

Gomes Teles, Ramon Handerson ^[1] ; Graminha, Angelica Ellen ^[1] ; Rivera-Cruz, Cosette M. ^[2] ; Nakahata, Douglas Hideki ^[3] ; Barboza Formiga, Andre Luiz ^[3] ; Corbi, Pedro Paulo ^[3] ; Figueiredo, Marxa Leao ^[2] ; Cominetti, Marcia Regina ^[1]

Affiliation

^[1] Univ Fed Sao Carlos, Dept Gerontol, Rod Washington Luis, Km 235, Sao Carlos, SP - Brazil

^[2] Purdue Univ, Dept Basic Med Sci, Coll Vet Med, 625 Harrison St, W Lafayette, IN 47907 - USA

^[3] Univ Estadual Campinas, Inst Chem, UNICAMP, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: TOXICOLOGY IN VITRO; v. 67, SEP 2020.
• Web of Science Citations: 0

Abstract

Cisplatin is widely used to treat different types of cancer, but its severe side effects are the major disadvantage of this treatment. Therefore, other metals are currently the subject of research in the rational development of anticancer drugs, such as copper, that has been demonstrated to be promising in this scenario. Here, we evaluated the effects of two novel copper complexes against breast cancer cell lines, and also examined the influence of overexpressing copper transporter 1 (CTR1) on the cytotoxicity of these complexes. Complex (1) {[}Cu (sdmx(-))(2)(phen)] showed low IC50 values, induced intense cell morphological changes and arrested the cell cycle at the sub-G1 phase in cancer cells. Complex (1) was tested in transfected cells overexpressing the CTR1 receptor in order to compare its steric effects with a less bulky ligand and more labile complex (2) {[}CuCl2(impy)]. A significant reduction of IC50 value was observed in CTR1 overexpressing cells for complex (2) (32 mu M to 20 mu M) as compared to (1) (2.78 mu M to 3.41 mu M), evidencing a possible uptake through copper reduction (Cu+2 -> Cu+1) mediated by CTR1. Thus, considering that CTR1 is a mediator of metallodrugs uptake, the development of strategies that use rational drug design is important in order to improve the therapeutic efficacy through greater specificity and consecutive reduction of side effects. Here we show the example for the case of copper(II) complexes. (AU)

• FAPESP's process: 18/12062-4 - Synthesis, characterization and studies of interaction with biomolecules of metal complexes containing biologically active ligands: a strategy in the preparation of new agents with antibacterial and antiviral activities
• Grantee: Pedro Paulo Corbi
• Support type: Regular Research Grants
• FAPESP's process: 15/20882-3 - Metal complexes of sulfamethoxydiazine and sulfadimethoxine: synthesis, characterization and applications as antimicrobial agents for topical use
• Grantee: Douglas Hideki Nakahata
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/17170-0 - Importance of the copper transporter 1 receptor in the uptake of the copper complex [Cu(sdmx)2(phen)] into triple negative breast tumor cells
• Grantee: Ramon Handerson Gomes Teles
• Support type: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/19504-0 - Evaluation of the activity of ruthenium complexes encapsulated in triple-negative breast tumor metastases
• Grantee: Ramon Handerson Gomes Teles
• Support type: Scholarships in Brazil - Master