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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: TOXICOLOGY IN VITRO; v. 67, SEP 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 18/12062-4 - Síntese, caracterização e estudos de interação com biomoléculas de complexos metálicos contendo ligantes biologicamente ativos: uma estratégia na preparação de novos agentes com atividades antibacterianas e antivirais
• Beneficiário: Pedro Paulo Corbi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/20882-3 - Complexos metálicos com sulfametoxidiazina e sulfadimetoxina: síntese, caracterização e aplicações como agentes antimicrobianos para uso tópico
• Beneficiário: Douglas Hideki Nakahata
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/17170-0 - Importância do receptor transportador de cobre 1 na captação do complexo de cobre [Cu (sdmx) 2 (phen)] em células tumorais de mama triplo negativo
• Beneficiário: Ramon Handerson Gomes Teles
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/19504-0 - Avaliação da atividade de complexos de rutênio encapsulados sobre metástases de tumor de mama triplo negativo
• Beneficiário: Ramon Handerson Gomes Teles
• Modalidade de apoio: Bolsas no Brasil - Mestrado