Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
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]
Total Authors: 7
Affiliation:
[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
Total Affiliations: 5
Document type: Journal article
Source: FRONTIERS IN ONCOLOGY; v. 11, JUN 24 2021.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 17/15850-0 - X-ray diffraction as a tool in potential drug development
Grantee:Eduardo Ernesto Castellano
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 16/22429-7 - Toxicogenetics evaluation and study of antiproliferative response mechanisms of ruthenium-based metallodrugs containing naphthoquinones ligands in tumor cells growing in conventional and 3D systems
Grantee:Rone Aparecido de Grandis
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 18/00163-0 - Development and search of new antimicrobials against Tuberculosis: from screening to pre-clinical studies in vivo
Grantee:Fernando Rogério Pavan
Support Opportunities: Regular Research Grants