Ruthenium(II) complex with 2-mercaptothiazoline ligand induces selective cytotoxicity involving DNA damage and apoptosis in melanoma cells.

Melanoma is the most aggressive and lethal type of skin cancer due to its characteristics such as high metastatic potential and low response rate to existing treatment modalities. In this way, new drug prototypes are being studied to solve the problem of treating patients with melanoma. Among these, ruthenium-based metallopharmaceuticals may be promising alternatives due to their antitumor characteristics and low systemic toxicity. In this context, the present study evaluated the antineoplastic effect of the ruthenium complex [Ru(mtz)(dppe)2]PF6-2-mercaptothiazoline-di-1,2-bis(diphenylphosphine) ethaneruthenium(II), namely RuMTZ, on human melanoma (A-375) and murine (B16-F10) cells, considering different approaches. Through XTT colorimetric and clonogenic efficiency assays, the complex revealed the selective cytotoxic activity, with the lowest IC50 (0.4 µM) observed for A375 cells. RuMTZ also induced changes in cell morphology, increased cell population in the sub-G0 phase and inhibiting cell migration. The levels of γH2AX and cleaved caspase 3 proteins were increased in both cell lines treated with RuMTZ. These findings indicated that the cytotoxic activity of RuMTZ on melanoma cells is related, at least in part, to the induction of DNA damage and apoptosis. Therefore, RuMTZ exhibited promising antineoplastic activity against melanoma cells.

Efficacy and safety of guttiferone E in melanoma-bearing mice.

Melanoma, an aggressive and potentially fatal skin cancer, is constrained by immunosuppression, resistance, and high toxicity in its treatment. Consequently, there is an urgent need for innovative antineoplastic agents. Therefore, this study investigated the antimelanoma potential of guttiferone E (GE). In an allogeneic murine B16 melanoma model, GE was administered subcutaneously and intraperitoneally. Antitumor evaluation included tumor volume/weight measurements and histopathological and immunohistochemical analysis. Furthermore, the toxicity of the treatments was evaluated through body/organ weights, biochemical parameters, and genotoxicity. Subcutaneous administration of 20 mg/kg of GE resulted in a significant reduction in both tumor volume and weight, effectively suppressing melanoma cell proliferation as evidenced by a decrease in mitotic figures. The tumor growth inhibition rate was equivalent to 54%. This treatment upregulated cleaved caspase-3, indicating apoptosis induction. On the other hand, intraperitoneal administration of GE showed no antimelanoma effect. Remarkably, GE treatments exhibited no toxicity, evidenced by non-significant differences in body weight gain, as well as organ weight, biochemical parameters of nephrotoxicity and hepatotoxicity, and genotoxic damage. This study revealed, for the first time, the efficacy of subcutaneous administration of GE in reducing melanoma, in the absence of toxicity. Furthermore, it was observed that the apoptotic signaling pathway is involved in the antimelanoma property of GE. These findings offer valuable insights for further exploring GE's therapeutic applications in melanoma treatment.

Pharmacokinetic study of AmB-NP-GR: A new granule form with amphotericin B to treat leishmaniasis and fungal infections.

Amphotericin B (AmB) has been the gold standard to treat systemic fungal infections. The use of AmB is restricted to hospitals because it poses several risks, mainly risks related to its high nephrotoxicity. Given the importance of this drug in medicine, new therapeutics and AmB formulations with nanotechnological improvements are required and could bring many benefits to patients. A new drug formulation with gastro-resistant coated granules has been proposed. The lipid-based system containing AmB was produced and used as raw material in the granulation/coated process. The new developed formulation (AmB-NP-GR) was characterized by optical microscopy, granulometry, and atomic force microscopy (AFM) after disintegration test. AmB-NP-GR showed granular shape, with most granules measured between 250 and 500 µm (37 ± 7% w/w). The AFM images indicated that the granule formulation should disintegrate in the intestine, to release the lipid-based carriers, making them available for absorption and allowing them to reach the blood circulation. The developed formulation was administered to rats in a single dose of 4.0 or 8.0 mg kg-1 and the pharmacokinetics was studied. The samples were analyzed by liquid chromatography coupled to mass spectrometry. Before the pharmacokinetic studies were conducted, the bioanalytical method was validated according to the EMA guideline and all evaluated parameters agreed with this guideline. The pharmacokinetic results showed that Cmax was similar for both doses and that tmax was reached at 4-12 h for dose of 4.0 mg kg-1 and 4 h for dose of 8.0 mg kg-1. The half-life related to the dose of 8.0 mg kg-1 increased significantly compared to the dose of 4.0 mg kg-1 (an increase of more than 3 times). In addition, the mean residence time related to the dose of 8.0 mg kg-1 was 4 times higher than for the lower dose. The clearance value showed to be higher for the lower dose. Together, these results provide important conclusions for experimental design of other in vivo safety and efficacy studies of AmB-NP-GR.

Red propolis exhibits chemopreventive effect associated with antiproliferative and anti-inflammatory activities.

INTRODUCTION: Red propolis is synthetized from exudates of Dalbergia ecastophyllum (L) Taub. and Symphonia globulifera L.f., presents isoflavones, guttiferone E, xanthochymol, and oblongifolin B and has anti-inflammatory, antioxidant, and antiproliferative activities. OBJECTIVES: This study aimed to evaluate the antigenotoxic and anticarcinogenic potential of red propolis hydroalcoholic extract (RPHE) in rodents. METHODS: The influence of RPHE in doxorubicin (DXR)-induced genotoxicity was investigated through the micronucleus test in Swiss mice. Blood samples were also collected to investigate oxidative stress, hepatotoxicity, and nephrotoxicity. Was investigated the influence of RPHE in 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci, as well as its influence in proliferating cell nuclear antigen (PCNA) and the cyclooxygenase-2 (COX-2) expression in colon of rats, by immunohistochemistry. RESULTS: The results showed that RPHE (48 mg/kg) reduced DXR-induced genotoxicity. Animals treated with DXR showed significantly lower GSH serum levels in comparison to the negative control. RPHE treatments did not attenuated significantly the DXR-induced GSH depletion. No difference was observed in cytotoxicity parameters of mice hematopoietic tissues between the treatment groups, as well as the biochemical parameters of hepatotoxicity and nephrotoxicity. RPHE (12 mg/kg) reduced the DMH-induced carcinogenicity and toxicity, as well as DMH-induced PCNA and COX-2 expression in colon tissue. CONCLUSION: Therefore, was observed that the RPHE has chemopreventive effect, associated to antiproliferative and anti-inflammatory activities.

Toxicological and chemoprevention studies of Dalbergia ecastaphyllum (L.) Taub. stem, the botanical source of Brazilian red propolis.

OBJECTIVES: Dalbergia ecastaphyllum (L.) Taub. is a semi-prostrate species associated with estuaries, mangroves and dunes. This plant species has great ecological and economic importance, especially concerning apiculture pasture and Brazilian red propolis production. In this study, non-clinical toxicological evaluations of the hydroalcoholic extract of D. ecastaphyllum stems (DEHE), the resin production source, were conducted. In addition, the action of DEHE on genomic instability and colon carcinogenesis was investigated. METHODS AND RESULTS: The extract's chemical profile was analysed by HPLC, and medicarpin, vestitol and neovestitol were found as major compounds. DEHE showed an IC50 equivalent to 373.2 µg/ml and LC50 equal 24.4 mg/L, when evaluated using the XTT colorimetric test and the zebrafish acute toxicity assay, respectively. DEHE was neither genotoxic nor cytotoxic at the highest dose, 2000 mg/kg, by peripheral blood micronucleus test. The treatments DEHE (6 and 24 mg/kg) led to the reduction of micronuclei induced by doxorubicin (DXR) in mice. Furthermore, significantly higher serum levels of reduced glutathione were observed in animals treated with DEHE plus DXR, revealing an antioxidant effect. Treatments with DEHE (48 mg/kg) led to a significant reduction in pre-neoplastic lesions induced by the 1,2-dimethylhydrazine (DMH) carcinogen in the rat colon. Immunohistochemical analysis revealed significantly lower levels of expression of COX-2 (86%) and PCNA (83%) in the colon of rats treated with DEHE plus DMH, concerning those treated with the carcinogen. CONCLUSIONS: These results indicate the involvement of anti-inflammatory and antiproliferative pathways in the protective effect of DEHE.