Browsing by Author "Bomfim, Larissa Mendes"

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    Cytotoxic potential of 14 Passiflora species against cancer cells.
    (2019) Amaral, Ricardo Guimarães; Gomes, Silvana Vieira Floresta; Luciano, Maria Claudia dos Santos; Pessoa, Claudia do Ó; Andrade, Luciana Nalone; Severino, Patrícia; Brandão, Geraldo Célio; Bomfim, Larissa Mendes; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira; David, Jorge Maurício; Carvalho, Adriana Andrade
    This work aimed to evaluate the cytotoxic potential against cancer cells of Passiflora genus plant species cultivated in Brazil and identify the mechanism of cytotoxicity induced by the most promising extract. Ethanolic extracts from the leaves of 14 Passiflora species were obtained by accelerated solvent extraction and in vitro cytotoxicity evaluated against cancer cell lines using MTT assay at a single concentration of 50 μg/ml. Additionally, the IC50 of the Passiflora alata (ELPA) leaf extracts was determined against both cancer (HCT-116, SF-295, OVACAR-8, and HL-60), and non-cancer cells (PBMC). The ELPA flavonoids were identified by HPLC-DAD and UHPLC-MS/MS. The morphological analyses, using light and fluorescence microscopy, and cell cycle and DNA fragmentation analysis, using flow cytometry, were evaluated to study the mechanism of cell death induced by ELPA in HL-60 cells. Among the Passiflora leaf extracts evaluated; ELPA stood out with high cytotoxic activity, followed by Passiflora capsularis and Passiflora quadrangularis with varying high and low cytotoxic activity. ELPA presented high cytotoxic potency in HL-60 (IC50 19.37 μg/ml), and without cytotoxicity against PBMC, suggesting selectivity for cancer cells. The cytotoxic activity of ELPA may well be linked to the presence of ten identified flavonoids. Cells treated with ELPA presented the hallmarks typical of apoptosis and necrosis, with cell cycle arrest in the G2/M phase. From among the studied species, ELPA presented greater cytotoxic activity, possibly a consequence of synergistic flavonoid action, which induces cell death by apoptosis and necrosis.
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    Nucleobase derivatives as building blocks to form Ru(II)-based complexes with high cytotoxicity.
    (2020) Carvalho, Diogo Émerson Leite de; Oliveira, Katia Mara de; Bomfim, Larissa Mendes; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira; Batista, Alzir Azevedo; Correa, Rodrigo de Souza
    Two new Ru(II)-based complexes containing 2-thiouracil derivatives, known as 2-thiouracil (2TU) and 6-methyl-2-thiouracil (6m2TU), were synthesized using cis,trans-[RuCl2(PPh3)2(bipy)] as a precursor. The obtained compounds with a general formula trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) were characterized by analytical techniques such as NMR, UV–vis, and IR spectroscopies, elementary analysis, mass spectrometry, and single-crystal X-ray diffraction. Moreover, the investigation of the complexes–DNA interaction were carried out using spectrophotometric titrations and showed that the complexes present a weak interaction with this biomolecule. The compounds were evaluated against HL-60, K-562, HepG2, and B16-F10 cancer cells and against noncancer cells (PBMCs). The results of the biological assay revealed that complex 2 is more promising than complex 1. Finally, the present study suggests that complexes 1 and 2 causes cell death by apoptosis, significantly increasing the percentage of apoptotic HL-60 cells, in which the compounds altered the cell cycle, reducing the cells in G1/G0, G2/M, and S phases.
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    Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.
    (2019) Correa, Rodrigo de Souza; Bomfim, Larissa Mendes; Oliveira, Katia Mara de; Moreira, Diogo Rodrigo de Magalhães; Soares, Milena Botelho Pereira; Ellena, Javier Alcides; Bezerra, Daniel Pereira; Batista, Alzir Azevedo
    We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh3)2(2TU)2] (1), [Ru(PPh3)2(6m2TU)2] (2), [Ru(dppb)(2TU)2] (3) and [Ru(dppb)(6m2TU)2] (4), where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV–vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1–4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8–1.8 × 104 M−1. Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A – human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds.
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    Ru(II)–thyminate complexes : new metallodrug candidates against tumor cells.
    (2018) Correa, Rodrigo de Souza; Freire, Vitória; Barbosa, Marília Imaculada Frazão; Bezerra, Daniel Pereira; Bomfim, Larissa Mendes; Moreira, Diogo Rodrigo de Magalhães; Soares, Milena Botelho Pereira; Ellena, Javier Alcides; Batista, Alzir Azevedo
    Herein, we used thymine (HThy) as a ligand to form two new ruthenium(II) complexes with formula [Ru(PPh3)2(Thy)(bipy)]PF6 (1) and [Ru(Thy)(bipy)(dppb)]PF6 (2). The complexes were characterized by spectroscopic, spectrometric and X-ray crystallography analyses. Complexes 1 and 2 can interact with ctDNA presenting binding constants, Kb, of 0.4 and 1.2 × 103 M−1, respectively. Their cytotoxic activities towards tumor cell lines (B16-F10, HepG2, K562 and HL-60) and non-tumor cells (PBMCs) were evaluated using the Alamar blue assay. Complex 1 exhibits high cytotoxicity against tumor cells, showing IC50 values of 0.01 and 1.81 μM against the HL-60 and HepG2 cell lines, respectively. Therefore, compound 1 can be considered as a promising antitumor metallodrug.
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    Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells.
    (2019) Bomfim, Larissa Mendes; Araujo, Fênix Alexandra de; Dias, Rosane Borges; Sales, Caroline Brandi Schlaepfer; Rocha, Clarissa Araújo Gurgel; Correa, Rodrigo de Souza; Soares, Milena Botelho Pereira; Batista, Alzir Azevedo; Bezerra, Daniel Pereira
    Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.