ABSTRACT
Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 µM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 µM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA).
Subject(s)
Antineoplastic Agents , Coordination Complexes , DNA , Rhenium , Rhenium/chemistry , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , DNA/chemistry , DNA/metabolism , Phenanthrolines/chemistry , Phenanthrolines/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Phenazines/chemistry , Phenazines/pharmacology , Cell Line, Tumor , HeLa CellsABSTRACT
Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men worldwide. The treatment of advanced cases is based on chemotherapy, which lacks specificity and efficacy, due to severe side effects and resistance to the traditional drugs. Copper complexes have shown antitumoral efficacy and low toxicity, being considered a promising class of metal-based drugs for the treatment of malignant neoplasms. Thus, the present study aimed to evaluate the cellular effects of a copper(II) complex with 4-fluorophenoxyacetic acid hydrazide and 1,10-phenanthroline (1) on PCa cell lines, as well as the mutagenic/recombinogenic and anticarcinogenic potential of 1 in Drosophila melanogaster. PNT-2 (non-tumorigenic), LNCaP (hormone-responsive PCa) and PC-3 (androgen-independent PCa) cells were cultured, and cytotoxicity was assessed using the MTT assay. The expression levels of the proliferation markers Ki-67 and Cyclin D1 were analyzed by flow cytometry. Furthermore, the Somatic Mutation and Recombination Test (SMART) and the Epithelial Tumor Test (ETT) were performed. Complex 1 was selective to LNCaP cells, significantly reducing Ki-67 and Cyclin D1 expression levels. Sub-toxic concentrations of complex 1 were defined by the toxicity test in D. melanogaster, and no mutagenic/recombinogenic/carcinogenic effects were observed. Anticarcinogenic potential was observed in D. melanogaster, suggesting modulating activity of the complex 1 against Doxorubicin, a drug used as control by its carcinogenic properties. Therefore, complex 1 is a possible starting point for the development of new antitumor agents for the treatment of PCa.
Subject(s)
Antineoplastic Agents , Prostatic Neoplasms , Humans , Male , Animals , Drosophila melanogaster , Copper/pharmacology , Cyclin D1 , Hydrazines/pharmacology , Androgens/pharmacology , Ki-67 Antigen , Prostatic Neoplasms/pathology , Mutagens/pharmacology , Carcinogenesis , Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Cell Line, Tumor , DNA-Binding Proteins/pharmacologyABSTRACT
Garcinia humilis, known commonly as achachairú or bacupari, has great medicinal value. Their fruits have pharmacological, antibacterial, antioxidant, and anticancer properties. Therefore, the objective of the present study was to evaluate the cytotoxicity and genotoxicity of G. humilis crude extract in breast tumor cells. Cytotoxicity was determined using the Resazurin reduction assay and genotoxicity by the single cell gel electrophoresis assay (Comet assay) on human MCF-7 cells. Crude extract of G. humilis was cytotoxic only when used at high concentrations (IC50 = 5.084 mg mL-1). The Comet assay showed that the crude extract did not induce genotoxicity at 1 and 5 mg mL-1 but did show signs of DNA fragmentation and DNA fragmentation at 10 mg mL-1. The cytotoxic activity against breast adenocarcinoma cells at high concentrations suggests that this medicinal plant could be used with caution and must be further studied to understand better its therapeutic and toxicological potential in the human body.
Subject(s)
Anticarcinogenic Agents , Garcinia , AntioxidantsABSTRACT
The thin line between efficacy and toxicity has challenged cancer therapy. As copper is an essential micronutrient and is important to tumor biology, CuII complexes emerged as an alternative to chemotherapy; however, its biological properties need to be better understood. Thus, we report in vitro the antitumor effects of two CuII complexes named [Cu(4-fh)(phen)(ClO4)2] (complex 1) and [Cu(4-nh)(phen)(ClO4)2]·H2O (complex 2), in which 4-fh = 4-fluorophenoxyacetic acid hydrazide; 4-nh = 4-nitrobenzoic hydrazide and phen = 1,10-phenanthroline. Both complexes presented cytotoxic activity against tumor cells, but only complex 1 showed significant selectivity. Complex 1 also induced DNA-damage, led to G0/G1 arrest and triggered apoptosis, which was initiated by an autophagy dysfunction. The significant in vitro selectivity and the action mechanism of complex 1 are noteworthy and reveal this prodrug as promising for anticancer therapy.
