Advances in the treatment of Chagas disease: Promising new drugs, plants and targets.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

/pdf/cytotoxicity-and-anti-tumor-effects-of-new-ruthenium-36j4rt3j37.pdf

Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells

Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Fundacao de Amparo a Pesquisa do Estado da
Bahia (FAPESB) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP).

/pdf/novel-piplartine-containing-ruthenium-complexes-synthesis-3u8l0022uw.pdf

Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells.

Chagas Disease caused by Trypanosoma cruzi infection, is one of the most important neglected tropical diseases (NTD), without an effective therapy for the successful parasite eradication or for the blocking of the disease’s progression, in its advanced stages. Due to their low toxicity, wide pharmacologic spectrum, and potential synergies, medicinal plants as Lippia alba, offer a promising reserve of bioactive molecules. The principal goal of this work is to characterize the inhibitory properties and cellular effects of the Citral and Carvone L. alba chemotype essential oils (EOs) and their main bioactive terpenes (and the synergies among them) on T. cruzi forms. Twelve L. alba EOs, produced under diverse environmental conditions, were extracted by microwave assisted hydrodistillation, and chemically characterized using gas chromatography coupled mass spectrometry. Trypanocidal activity and cytotoxicity were determined for each oil, and their major compounds, on epimastigotes (Epi), trypomastigotes (Tryp), amastigotes (Amas), and Vero cells. Pharmacologic interactions were defined by a matrix of combinations among the most trypanocidal terpenes (limonene, carvone; citral and caryophyllene oxide). The treated cell phenotype was assessed by fluorescent and optic microscopy, flow cytometry, and DNA electrophoresis assays. The L. alba EOs displayed significant differences in their chemical composition and trypanocidal performance (p = 0.0001). Citral chemotype oils were more trypanocidal than Carvone EOs, with Inhibitory Concentration 50 (IC50) of 14 ± 1.5 μg/mL, 22 ± 1.4 μg/mL and 74 ± 4.4 μg/mL, on Epi, Tryp and Amas, respectively. Limonene exhibited synergistic interaction with citral, caryophyllene oxide and Benznidazole (decreasing by 17 times its IC50) and was the most effective and selective treatment. The cellular analysis suggested that these oils or their bioactive terpenes (citral, caryophyllene oxide and limonene) could be inducing T. cruzi cell death by an apoptotic-like mechanism. EOs extracted from L. alba Citral chemotype demonstrated significant trypanocidal activity on the three forms of T. cruzi studied, and their composition and trypanocidal performance were influenced by production parameters. Citral, caryophyllene oxide, and limonene showed a possible induction of an apoptotic-like phenotype. The best selective anti-T. cruzi activity was achieved by limonene, the effects of which were also synergic with citral, caryophyllene oxide and benznidazole.

/pdf/induction-of-programmed-cell-death-in-trypanosoma-cruzi-by-4peaiq63xi.pdf

Induction of programmed cell death in Trypanosoma cruzi by Lippia alba essential oils and their major and synergistic terpenes (citral, limonene and caryophyllene oxide)

The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis.

https://www.arca.fiocruz.br/bitstream/icict/13713/2/Meira%2c%20CS%20In%20vitro%20and%20.....pdf

In vitro and in vivo antiparasitic activity of Physalis angulata L. concentrated ethanolic extract against Trypanosoma cruzi.

https://www.arca.fiocruz.br/bitstream/icict/14266/2/Correa%20RS%20Ruthenium%20%28II%29....pdf

Ruthenium(II) complexes of 1,3-thiazolidine-2-thione: Cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole.

Investigation by GC-FID and GC-MS of the essential oil (LPOE) from the leaves of Lippia pedunculosa revealed, as the major compounds, the monoterpenes rotundifolone (71.7%) and (R)-limonene (21.8%). These two compounds and the minor constituent piperitenone (1.2%) were also isolated from the leaves and identified by spectrometric analysis. LPOE and isolated compounds were evaluated for their trypanocidal activity against epimastigote and trypomastigote forms of Trypanosoma cruzi. Significant results with IC50 values lower than 34.0 microg.mL(-1) were observed against these forms of T. cruzi for LPOE and isolated compounds. Rotundifolone was the most active compound with an ICso lower than 10.0 ig.mL"' for both forms of T. cruzi. The effects of LPOE and isolated compounds were also evaluated in cultures of macrophages infected with T. cruzi. Treatment with (R)-limonene and rotundifolone caused a moderate reduction in the percentage of macrophages infected by T. cruzi and in the number of intracellular parasites at concentrations non-toxic to macrophages.

/pdf/a-new-source-of-r-limonene-and-rotundifolone-from-leaves-of-2j17u5mb4j.pdf

A New Source of (R)-Limonene and Rotundifolone from Leaves of Lippia pedunculosa (Verbenaceae) and their Trypanocidal Properties

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Papers

In vitro and in vivo antiparasitic activity of Physalis angulata L. concentrated ethanolic extract against Trypanosoma cruzi.

Ruthenium(II) complexes of 1,3-thiazolidine-2-thione: Cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole.

A New Source of (R)-Limonene and Rotundifolone from Leaves of Lippia pedunculosa (Verbenaceae) and their Trypanocidal Properties