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

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.

Anticancer activities of Brachydin C in human prostate tumor cells (DU145) grown in 2D and 3D models: Stimulation of cell death and downregulation of metalloproteinases in spheroids

“…BrC was time‐dependent cytotoxic to DU145 spheroids in the resazurin assay, with an IC 50 almost five times higher than that found in a 2D model. Similar results were reported by De Grandis et al (2021) who treated DU145 cells with cisplatin for 24 h and the drug resistance of DU145 cells was three times higher in MCTS than in 2D culture. These findings confirm how cells grown in 2D and 3D models behave differently.…”

HPMCAS-Coated Alginate Microparticles Loaded with Ctx(Ile21)-Ha as a Promising Antimicrobial Agent against Salmonella Enteritidis in a Chicken Infection Model

“…In the evaluation of the monolayer permeability of Caco-2 cells, it was found that the single layer was formed satisfactorily and that the mean transepithelial electrical resistance (TEER) value was 579.44 ± 38.75 Ω·cm 2 . Values greater than 300 Ω·cm 2 are known to be the most optimal for cell permeability assays . In addition, 1 mL aliquots were collected at different times from the basolateral compartment of monolayer cells.…”

“…Values greater than 300 Ω• cm 2 are known to be the most optimal for cell permeability assays. 31 In addition, 1 mL aliquots were collected at different times from the basolateral compartment of monolayer cells. The study of the peptide concentration of the microparticles, after exposure to the cell monolayer, showed the presence of the peptide through the monolayer of 69.29% and 100% of B and C microparticles, respectively, up to 360 min, calculated using Nanodrop equipment (Figure 4).…”

“…Briefly, microparticles were incubated at 40 °C with slow shaking for 20/60 min in 0.1 mol L –1 HCl at pH 3.5 and 6. Subsequently, and based on the protocol by De Grandis et al, samples were diluted in Hank’s salt solution to 2 mg mL –1 (a previously calculated cytotoxicity value) and incubated on the monolayer of Caco-2 cells. Finally, 1 mL of the solution/Hank’s salt was collected/replaced from the basolateral compartment at 0, 15, 30, 60, 120, and 180 min.…”

Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

“…For instance, findings suggested that the natural compound lapachol inhibited PKM2, inducing a blockade of glycolysis, decreasing ATP levels and sensitizing melanoma cells to apoptosis [ 211 ]. In addition, in prostate cancers lapachol promotes apoptosis by inducing increase in ROS production and in the transcription of caspase-3 and -9 [ 212 ]. Apoptosis induction by lapachol was also observed in tumors of different histology [ 213 , 214 ].…”