A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

Autor(es)

De Grandis, Rone A. ^{[1, 2]} ; Oliveira, Katia M. ^[3] ; Guedes, Adriana P. M. ^[3] ; dos Santos, Patrick W. S. ^[4] ; Aissa, Alexandre F. ^[5] ; Batista, Alzir A. ^[3] ; Pavan, Fernando R. ^[1]

Afiliação do(s) autor(es)

^[1] Sao Paulo State Univ, Sch Pharmaceut Sci, Araraquara, SP - Brazil

^[2] Univ Araraquara, Sch Med, Araraquara, SP - Brazil

^[3] Univ Fed Sao Carlos, Dept Chem, Sao Carlos - Brazil

^[4] Univ Sao Paulo, Sch Med Ribeirao Preto, Ribeirao Preto - Brazil

^[5] Univ Illinois, Coll Med, Dept Biochem & Mol Genet, Chicago, IL - USA

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN ONCOLOGY; v. 11, JUN 24 2021.
• Citações Web of Science: 0

Resumo

Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes {[}Ru(Lap)(dppm)(bipy)]PF6 (1) and {[}Ru(Lap)(dppm)(phen)]PF6 (2) {[}Lap = lapachol, dppm = 1,1 `-bis(diphosphino)methane, bipy = 2,2 `-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex (2) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex (2) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (2), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy. (AU)

• Processo FAPESP: 17/15850-0 - Difração de raios X como ferramenta no desenvolvimento de potenciais fármacos
• Beneficiário: Eduardo Ernesto Castellano
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/22429-7 - Avaliação toxicogenética e estudo dos mecanismos de resposta antiproliferativa de metalofármacos de rutênio contendo bioligantes naftoquinônicos em modelos celulares tumorais convencionais e em 3D
• Beneficiário: Rone Aparecido de Grandis
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/00163-0 - Desenvolvimento e busca de novos antimicrobianos contra Tuberculose: da triagem a estudos pré-clínicos in vivo
• Beneficiário: Fernando Rogério Pavan
• Modalidade de apoio: Auxílio à Pesquisa - Regular