nti-melanoma effect of ruthenium(II)-diphosphine complexes containing naphthoquinone ligan

Author(s)

Rinaldi-Neto, Francisco ^[1] ; Ribeiro, Arthur Barcelos ^[1] ; Ferreira, Natalia Helen ^[1] ; Squarisi, Iara Silva ^[1] ; Oliveira, Katia Mara ^[2] ; Orenha, Renato Pereira ^[1] ; Tame Parreira, Renato Luis ^[1] ; Batista, Alzir Azevedo ^[2] ; Tavares, Denise Crispim ^[1]

Affiliation

^[1] Univ Franca, Ave Dr Armando Salles Oliveira, 201 Parque Univ, BR-14404600 Franca, SP - Brazil

^[2] Univ Fed Sao Carlos, Dept Quim, Rodovia Washington Luis S-N Km 235, BR-13565905 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: Journal of Inorganic Biochemistry; v. 222, SEP 2021.
• Web of Science Citations: 1

Abstract

The use of natural products as potential ligands has been explored as a strategy in the development of metal-based chemotherapy. Since ruthenium complexes are promising alternatives to traditional antitumor agents, this study evaluated the anti-melanoma potential of two ruthenium(II) complexes containing the naphthoquinone ligands lapachol (lap), {[}Ru(lap)(dppm)(2)]PF6, and lawsone (law), {[}Ru(law)(dppm)(2)]PF6, in addition to the bis(diphenylphosphino)methane (dppm) ligand, referred to as complexes (1) and (2), respectively, using a syngeneic murine melanoma model. Activation of the apoptotic pathway by the treatments was assessed by immunohistochemistry in tumor tissue. Additionally, toxicity of the treatments was evaluated by variation in body and organ weight, quantification of biochemical indicators of renal damage, and genotoxicity in bone marrow and hepatocytes. First, the antiproliferative activity of (1) and (2) was observed in B16F10 cells, with IC50 values of 2.78 and 1.68 mu M, respectively. The results obtained in mice showed that, unlike complex (1), (2) possesses significant anti-melanoma activity demonstrated by a reduction in tumor volume and mass (88.42%), as well as in mitosis frequency (83.86%). Additionally, complex (2) increased the levels of cleaved caspase-3, inducing tumor cell apoptosis. When compared to the metallodrug cisplatin, complex (2) exhibited similar anti-melanoma activity and lower toxicity considering all parameters evaluated. In silico studies demonstrated no difference in the binding energy of the naphthoquinone complex between complexes (1) and (2). However, the complex containing the lawsone ligand has a lower molar volume, which may be important for interactions with minor DNA grooves. The present results demonstrate the antitumor efficiency of complex (2) and a significantly lower systemic toxicity compared to cisplatin. (AU)

• FAPESP's process: 16/24269-7 - Analysis of the effects of manool, a diterpene of Salvia officinalis, on cell and genomic integrity.
• Grantee: Denise Crispim Tavares
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/19342-2 - Metal complexes with dirivative ligands of lawsone and acylthioureas, with anticancer potential activities: study in vitro and in vivo.
• Grantee: Alzir Azevedo Batista
• Support Opportunities: Regular Research Grants