Three-dimensional cell culture models for metallodrug testing: induction of apoptosis and phenotypic reversion of breast cancer cells by the trans-[Ru(PPh3)(2)(N,N-dimethyl-N-thiophenyl-thioureato-k(2)O,S)(bipy) ]PF6 complex

Autor(es)

Becceneri, Amanda B. ^[1] ; Fuzer, Angelina M. ^[1] ; Plutin, Ana M. ^[2] ; Batista, Alzir A. ^[3] ; Lelievre, Sophie A. ^{[4, 5]} ; Cominetti, Marcia R. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos, Dept Gerontol, Rod Washington Luis, Km 235, BR-13565905 Sao Carlos - Brazil

^[2] Univ La Habana, Fac Quim, Zapata S-N Entre G & Carlitos, Havana 10400 - Cuba

^[3] Univ Fed Sao Carlos, Dept Chem, Rod Washington Luis, Km 235, BR-13565905 Sao Carlos, SP - Brazil

^[4] Purdue Univ, Dept Basic Med Sci, 625 Harrison St, W Lafayette, IN 47907 - USA

^[5] Purdue Univ, Ctr Canc Res, 625 Harrison St, W Lafayette, IN 47907 - USA

• Tipo de documento: Artigo Científico
• Fonte: INORGANIC CHEMISTRY FRONTIERS; v. 7, n. 16, p. 2909-2919, AUG 21 2020.
• Citações Web of Science: 4

Resumo

Many studies have revealed the advantages of using three-dimensional (3D) culture over traditional twodimensional (2D) monolayer techniques. The 3D cell culture models represent biologically relevant approaches to better mimic the tumor organization observed in vivo. These models have high potential for anticancer drug development and screening, for which challenges include tumor cell resistance to treatment and the risk of toxicity for patients. Many anticancer drug candidates do not reach clinical trials as they fail preclinical tests in vivo, although they were promising in 2D cultures. Models from 3D cell cultures are proposed as intermediate screening filters between 2D and in vivo assays. It has been suggested that ruthenium complexes have great potential for breast cancer treatment. Here, we tested the trans{[}Ru(PPh3)(2)(N,N-dimethyl-N-thiophenylthioureato-k(2)O,S)(bipy)]P F6 complex in breast cancer cell lines using different 3D culture techniques, including the embedded, `on top' and disease-on-a-chip (DOC) models that reproduce physical aspects of the tumor microenvironment. The complex had pronounced but distinct cytotoxic effects on tumors cultured in collagen I of appropriate stiffness for the disease stage; the extent of induced apoptosis depends on the preinvasive (S2 cells) and invasive (T4-2 and MDA-MB-231 cells) nature of triple-negative breast cancer models. Remarkably, in the DOC model, which simulates breast ductal architecture, the complex was cytotoxic for T4-2 tumors but had no remarkable effect on the differentiated luminal epithelial S1 cells, demonstrating selectivity against cancer cells. In addition, a lower concentration of the complex abrogated the malignant phenotype of the T4-2 cells with reduction of EGFR, p50 NF kappa B, and beta 1-integrin expression. To the best of our knowledge, this work uniquely demonstrates the effects of a ruthenium complex on the induction of apoptosis and on the phenotypic reversion of tumor cells in 3D cultures. These results warrant moving to in vivo evaluation of this ruthenium complex. (AU)

• Processo FAPESP: 17/01287-2 - Triagem de compostos candidatos a novos medicamentos antitumorais por cultura celular tridimensional
• Beneficiário: Angelina Maria Fuzer
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/19342-2 - Complexos metalicos com ligantes derivados da lausona e aciltioureas, com potenciais atividades anticancerígenas: estudos in vitro e in vivo
• Beneficiário: Alzir Azevedo Batista
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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: 17/20055-5 - Efeitos do complexo de rutênio trans[Ru(ThySMet)(PPh3)2(bipy)]PF6 em células tumorais de mama em cultura tridimensional
• Beneficiário: Amanda Blanque Becceneri
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 15/24940-8 - Avaliação da eficácia de mudanças estruturais do [10]-gingerol em combinação com o quimioterápico doxorubicina para o tratamento de câncer de mama: estudos in vitro e in vivo
• Beneficiário: Márcia Regina Cominetti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/25121-8 - Atividade Antitumoral e Potencial Mutagênico de Novos Complexos de Rutênio
• Beneficiário: Amanda Blanque Becceneri
• Modalidade de apoio: Bolsas no Brasil - Doutorado