Publications by authors named "Rosane B Dias"

19 Publications

  • Page 1 of 1

A new synthetic antitumor naphthoquinone induces ROS-mediated apoptosis with activation of the JNK and p38 signaling pathways.

Chem Biol Interact 2021 Jul 30;343:109444. Epub 2021 Apr 30.

Laboratory of Biological Activity, Faculty of Pharmaceutical Sciences, Federal University of Amazonas - UFAM, Manaus, Amazonas, 69077-000, Brazil. Electronic address:

Quinones are plant-derived secondary metabolites that present diverse pharmacological properties, including antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activities. In the present study, we evaluated the cytotoxic effect of a new naphthoquinone 6b,7-dihydro-5H-cyclopenta [b]naphtho [2,1-d]furan-5,6 (9aH)-dione) (CNFD) in different tumor cell lines. CNFD displayed cytotoxic activity against different tumor cell lines, especially in MCF-7 human breast adenocarcinoma cells, which showed IC values of 3.06 and 0.98 μM for 24 and 48 h incubation, respectively. In wound-healing migration assays, CNFD promoted inhibition of cell migration. We have found typical hallmarks of apoptosis, such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of caspases-9 and-3 activation, increase of internucleosomal DNA fragmentation without affecting the cell membrane permeabilization, increase of ROS production, and loss of mitochondrial membrane potential induced by CNFD. Moreover, gene expression experiments indicated that CNFD increased the expression of the genes CDKN1A, FOS, MAX, and RAC1 and decreased the levels of mRNA transcripts of several genes, including CCND1, CDK2, SOS1, RHOA, GRB2, EGFR and KRAS. The CNFD treatment of MCF-7 cells induced the phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) and inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In a study using melanoma cells in a murine model in vivo, CNFD induced a potent anti-tumor activity. Herein, we describe, for the first time, the cytotoxicity and anti-tumor activity of CNFD and sequential mechanisms of apoptosis in MCF-7 cells. CNFD seems to be a promising candidate for anti-tumor therapy.
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http://dx.doi.org/10.1016/j.cbi.2021.109444DOI Listing
July 2021

Cell signaling pathways as molecular targets to eliminate AML stem cells.

Crit Rev Oncol Hematol 2021 Apr 11;160:103277. Epub 2021 Mar 11.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. Electronic address:

Acute myeloid leukemia (AML) remains the most lethal of leukemias and a small population of cells called leukemic stem cells (LSCs) has been associated with disease relapses. Some cell signaling pathways play an important role in AML survival, proliferation and self-renewal properties and are abnormally activated or suppressed in LSCs. This includes the NF-κB, Wnt/β-catenin, Hedgehog, Notch, EGFR, JAK/STAT, PI3K/AKT/mTOR, TGF/SMAD and PPAR pathways. This review aimed to discuss these pathways as molecular targets for eliminating AML LSCs. Herein, inhibitors/activators of these pathways were summarized as a potential new anti-AML therapy capable of eliminating LSCs to guide future researches. The clinical use of cell signaling pathways data can be useful to enhance the anti-AML therapy.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103277DOI Listing
April 2021

Glypican-1, -3, -5 (GPC1, GPC3, GPC5) and Hedgehog Pathway Expression in Oral Squamous Cell Carcinoma.

Appl Immunohistochem Mol Morphol 2021 May-Jun 01;29(5):345-351

Federal University of Bahia.

Proteoglycans are involved in tumor development and may regulate the Hedgehog (HH) pathway. This study aimed to investigate the gene and protein expression of glypican-1 (GPC1), -3 (GPC3), and -5 (GPC5) in oral squamous cell carcinoma (OSCC) and tumor-free lateral margins (TM) and their association with the HH pathway. Quantitative PCR was performed for GPC1, GPC3, GPC5, SHH, PTCH1, SMO, and GLI1 genes in samples of OSCC (n=31), TM (n=12), and non-neoplastic oral mucosa (NNM) of healthy patients (n=6), alongside an immunohistochemical evaluation of GPC1, GPC3, and GPC5 proteins and HH proteins SHH and glioma-associated oncogene homolog 1 (GLI1). Double staining for GPC3/SHH, GPC5/SHH, GPC3/tubulin [ac Lys40], GPC5/Tubulin [ac Lys40], and GPC5/GLI1 was also performed. Overexpression of GPC1 and GPC5 in tumor samples and underexpressed levels of GPC3 gene transcripts were observed when compared with TM (standard sample). HH pathway mRNA aberrant expression in OSCC samples and a negative correlation between GPC1 and GPC5 at transcription levels were detected. GPC1 staining was rare in OSCC, but positive cells were found in NNM and TM. Otherwise positive immunostaining for GPC3 and GPC5 was observed in OSCCs, but not in NNM and TM. Blood vessels adjacent to tumor islands were positive for GPC1 and GPC5. Co-localization of GPC3-positive and GPC5-positive cells with SHH and Tubulin [ac Lys40] proteins was noted, as well as of GPC5 and GLI1. The absence of the GPC1 protein in neoplastic cells, underexpression of the GPC3 gene, and co-localization of GPCs and HH proteins may indicate the maintenance of aberrant HH pathway activation in OSCC.
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http://dx.doi.org/10.1097/PAI.0000000000000907DOI Listing
June 2020

Essential Oil from Bark of Aniba parviflora (Meisn.) Mez (Lauraceae) Reduces HepG2 Cell Proliferation and Inhibits Tumor Development in a Xenograft Model.

Chem Biodivers 2021 Mar 15;18(3):e2000938. Epub 2021 Feb 15.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), 40296-710, Salvador, Bahia, Brazil or.

Aniba parviflora (Meisn.) Mez (Lauraceae) is an aromatic plant of the Amazon rainforest, which has a tremendous commercial value in the perfumery industry; it is popularly used as flavoring sachets and aromatic baths. In Brazilian folk medicine, A. parviflora is used to treat victims of snakebites. Herein, we analyzed the chemical composition of A. parviflora bark essential oil (EO) and its effect on the growth of human hepatocellular carcinoma HepG2 cells in vitro and in vivo. EO was obtained by hydrodistillation and characterized by GC-MS and GC-FID. The main constituents of EO were linalool (16.3±3.15), α-humulene (14.5±2.41 %), δ-cadinene (10.2±1.09 %), α-copaene (9.51±1.12 %) and germacrene B (7.58±2.15 %). Initially, EO's cytotoxic effect was evaluated against five cancer cell lines (HepG2, MCF-7, HCT116, HL-60 and B16-F10) and one non-cancerous one (MRC-5), using the Alamar blue method after 72 h of treatment. The calculated IC values were 9.05, 22.04, >50, 15.36, 17.57, and 30.46 μg/mL, respectively. The best selectivity was for HepG2 cells with a selective index of 3.4. DNA Fragmentation and cell cycle distribution were quantified in HepG2 cells by flow cytometry after a treatment period of 24 and 48 h. The effect of EO on tumor development in vivo was evaluated in a xenograft model using C.B-17 SCID mice engrafted with HepG2 cells. In vivo tumor growth inhibition of HepG2 xenograft at the doses of 40 and 80 mg/kg were 12.1 and 62.4 %, respectively.
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http://dx.doi.org/10.1002/cbdv.202000938DOI Listing
March 2021

Challenges and Therapeutic Opportunities of Autophagy in Cancer Therapy.

Cancers (Basel) 2020 Nov 20;12(11). Epub 2020 Nov 20.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Brazil.

Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells-while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed.
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http://dx.doi.org/10.3390/cancers12113461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699739PMC
November 2020

In vitro and in vivo inhibition of HCT116 cells by essential oils from bark and leaves of Virola surinamensis (Rol. ex Rottb.) Warb. (Myristicaceae).

J Ethnopharmacol 2020 Nov 27;262:113166. Epub 2020 Jul 27.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. Electronic address:

Ethnopharmacological Relevance: Virola surinamensis (Rol. ex Rottb.) Warb. (Myristicaceae), popularly known in Brazil as "mucuíba", "ucuúba", "ucuúba-branca" or "ucuúba do igapó", is a medicinal plant used to treat a variety of diseases, including infections, inflammatory processes and cancer.

Aim Of The Study: In the present work, we investigated the chemical constituents and the in vitro and in vivo inhibition of human colon carcinoma HCT116 cells by essential oils obtained from the bark (EOB) and leaves (EOL) of V. surinamensis.

Materials And Methods: EOB and EOL were obtained by hydrodistillation and analyzed via gas chromatography with flame ionization detection and gas chromatography coupled to mass spectrometry. In vitro cytotoxic activity was determined in cultured cancer cells HCT116, HepG2, HL-60, B16-F10 and MCF-7 and in a non-cancerous cell line MRC-5 by the Alamar blue assay after 72 h of treatment. Annexin V/propidium iodide staining, mitochondrial transmembrane potential and cell cycle distribution were evaluated by flow cytometry in HCT116 cells treated with essential oils after 24 and 48 h of treatment. The cells were also stained with May-Grunwald-Giemsa to analyze cell morphology. In vivo antitumor activity was evaluated in C.B-17 SCID mice with HCT116 cells.

Results: The main constituents in EOB were aristolene (28.0 ± 3.1%), α-gurjunene (15.1 ± 2.4%), valencene (14.1 ± 1.9%), germacrene D (7.5 ± 0.9%), δ-guaiene (6.8 ± 1.0%) and β-elemene (5.4 ± 0.6%). On the other hand, EOL displayed α-farnesene (14.5 ± 1.5%), β-elemene (9.6 ± 2.3%), bicyclogermacrene (8.1 ± 2.0%), germacrene D (7.4 ± 0.7%) and α-cubebene (5.6 ± 1.1%) as main constituents. EOB showed IC values for cancer cells ranging from 9.41 to 29.52 μg/mL for HCT116 and B16-F10, while EOL showed IC values for cancer cells ranging from 7.07 to 26.70 μg/mL for HepG2 and HCT116, respectively. The IC value for a non-cancerous MRC-5 cell was 34.7 and 38.93 μg/mL for EOB and EOL, respectively. Both oils induced apoptotic-like cell death in HCT116 cells, as observed by the morphological characteristics of apoptosis, externalization of phosphatidylserine, mitochondrial depolarization and fragmentation of internucleosomal DNA. At a dose of 40 mg/kg, tumor mass inhibition rates were 57.9 and 44.8% in animals treated with EOB and EOL, respectively.

Conclusions: These data indicate V. surinamensis as possible herbal medicine in the treatment of colon cancer.
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http://dx.doi.org/10.1016/j.jep.2020.113166DOI Listing
November 2020

Essential oil from leaves of Conobea scoparioides (Cham. & Schltdl.) Benth. (Plantaginaceae) causes cell death in HepG2 cells and inhibits tumor development in a xenograft model.

Biomed Pharmacother 2020 Sep 20;129:110402. Epub 2020 Jun 20.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. Electronic address:

Conobea scoparioides (Cham. & Schltdl.) Benth. (syn. Sphaerotheca scoparioides Cham. & Schldtl.) (Plantaginaceae), popularly known as "pataqueira", "vassourinha-do-brejo" and/or "hierba-de-sapo", is a popular medicinal plant used to treat leishmaniasis, pain and beriberi. In addition, inhibition of cell adhesion, antioxidant, cytotoxic and leishmanicidal activities of compounds or fractions of C. scoparioides have been reported. In the present work, chemical constituents and in vitro and in vivo anti-liver cancer potential of essential oil (EO) from leaves of C. scoparioides were investigated using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized by GC-MS and GC-FID. The in vitro cytotoxic effect was evaluated on three human cancer cell lines (MCF-7, HepG2 and HCT116) and one human non-cancerous cell line (MRC-5) using the Alamar blue assay. Phosphatidylserine externalization and cell cycle distribution were quantified in HepG2 cells by flow cytometry after 48 h incubation. The effectiveness of EO in anti-liver cancer model was studied with HepG2 cells grafted on C.B. 17 SCID mice. The main constituents of EO were thymol methyl ether (62 %), thymol (16 %) and α-phellandrene (14 %). EO displayed an in vitro cytotoxic effect against all human cancer cell lines and caused externalization of phosphatidylserine and DNA fragmentation in HepG2 cells, suggesting induction of apoptotic-like cell death. In vivo tumor mass inhibition of 36.7 and 55.8 % was observed for treatment with EO at doses of 40 and 80 mg/kg, respectively. These results indicate in vitro and in vivo anti-liver cancer potential of EO from leaves of C. scoparioides.
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http://dx.doi.org/10.1016/j.biopha.2020.110402DOI Listing
September 2020

L. (Cyperaceae) Rhizome Essential Oil Causes Cell Cycle Arrest in the G/M Phase and Cell Death in HepG2 Cells and Inhibits the Development of Tumors in a Xenograft Model.

Molecules 2020 Jun 9;25(11). Epub 2020 Jun 9.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Bahia, Salvador 40296-710, Brazil.

L. (Cyperaceae), popularly known in Brazil as "priprioca" or "piriprioca", is a tropical and subtropical plant used in popular medical practices to treat many diseases, including cancer. In this study, rhizome essential oil (EO), collected from the Brazilian Amazon rainforest, was addressed in relation to its chemical composition, induction of cell death in vitro and inhibition of tumor development in vivo, using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized qualitatively and quantitatively by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with flame ionization detection (GC-FID), respectively. The cytotoxic activity of EO was examined against five cancer cell lines (HepG2, HCT116, MCF-7, HL-60 and B16-F10) and one non-cancerous one (MRC-5) using the Alamar blue assay. Cell cycle distribution and cell death were investigated using flow cytometry in HepG2 cells treated with EO after 24, 48 and 72 h of incubation. The cells were also stained with May-Grunwald-Giemsa to analyze the morphological changes. The anti-liver-cancer activity of EO in vivo was evaluated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The main representative substances of this EO sample were muskatone (11.6%), cyclocolorenone (10.3%), α-pinene (8.26%), pogostol (6.36%), α-copaene (4.83%) and caryophyllene oxide (4.82%). EO showed IC values for cancer cell lines ranging from 28.5 µg/mL for HepG2 to >50 µg/mL for HCT116, and an IC value for non-cancerous of 46.0 µg/mL (MRC-5), showing selectivity indices below 2-fold for all cancer cells tested. HepG2 cells treated with EO showed cell cycle arrest at G/M along with internucleosomal DNA fragmentation. The morphological alterations included cell shrinkage and chromatin condensation. Treatment with EO also increased the percentage of apoptotic-like cells. The in vivo tumor mass inhibition rates of EO were 46.5-50.0%. The results obtained indicate the anti-liver-cancer potential of rhizome EO.
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http://dx.doi.org/10.3390/molecules25112687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321242PMC
June 2020

In vitro and in vivo growth inhibition of human acute promyelocytic leukemia HL-60 cells by Guatteria megalophylla Diels (Annonaceae) leaf essential oil.

Biomed Pharmacother 2020 Feb 30;122:109713. Epub 2019 Dec 30.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. Electronic address:

Guatteria megalophylla Diels (Annonaceae) is an 8-10 m tall tree that grows near streams and is widely spread throughout Colombian, Ecuadorian, Peruvian, Brazilian and Guianese Amazon rainforest. Herein, we investigated for the first time the chemical composition and in vitro and in vivo anti-leukemia potential of G. megalophylla leaf essential oil (EO) using human promyelocytic leukemia HL-60 cells as model. EO was obtained by a hydrodistillation clevenger-type apparatus and characterized quali- and quantitatively by GC-MS and GC-FID, respectively. In vitro cytotoxic potential of EO was evaluated in human cancer cell lines (HL-60, MCF-7 CAL27, HSC-3, HepG2 and HCT116) and in human non-cancer cell line (MRC-5) by Alamar blue method. Annexin V/propidium iodide staining, cell cycle distribution and reactive oxygen species (ROS) were assessed by flow cytometry for HL-60 cells treated with EO. In vivo efficacy of EO (50 and 100 mg/kg) was evaluated in C.B-17 SCID mice with HL-60 cell xenografts. Chemical composition analyses showed spathulenol, γ-muurolene, bicyclogermacrene, β-elemene and δ-elemene as main constituents of assayed sample. EO displayed in vitro cytotoxicity, including anti-leukemia effect with IC value of 12.51 μg/mL for HL-60 cells. EO treatment caused augment of phosphatidylserine externalization and DNA fragmentation without increasing of ROS in HL-60 cells. In vivo tumor mass inhibition rates of EO was 16.6-48.8 %. These data indicate anti-leukemia potential of G. megalophylla leaf EO.
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http://dx.doi.org/10.1016/j.biopha.2019.109713DOI Listing
February 2020

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.

Sci Rep 2019 08 7;9(1):11483. Epub 2019 Aug 7.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, Brazil.

Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)(PPh)] (1) and [Ru(6m2tu)(dppb)] (2) (where PPhtriphenylphosphine; 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.
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http://dx.doi.org/10.1038/s41598-019-47914-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686011PMC
August 2019

Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling.

Sci Rep 2019 07 31;9(1):11094. Epub 2019 Jul 31.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.

Ru(II)-thymine complex [Ru(PPh)(Thy)(bipy)]PF (where PPh = triphenylphosphine, Thy = thyminate and bipy = 2,2'-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6-40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate.
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http://dx.doi.org/10.1038/s41598-019-47539-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668648PMC
July 2019

Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells.

Front Oncol 2019 9;9:562. Epub 2019 Jul 9.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.

Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF (), [Ru(tzdt)(bipy)(dppb)]PF (), [Ru(dmp)(bipy)(dppb)]PF () and [Ru(mpca)(bipy)(dppb)]PF () were investigated for their cellular and molecular effects in cancer cell lines. Complexes and were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment.
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http://dx.doi.org/10.3389/fonc.2019.00562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629894PMC
July 2019

Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model.

Front Oncol 2019 3;9:582. Epub 2019 Jul 3.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Brazil.

Ruthenium complexes with piplartine, [Ru(piplartine)(dppf)(bipy)](PF) () and [Ru(piplartine)(dppb)(bipy)](PF) () (dppf = 1,1-bis(diphenylphosphino) ferrocene; dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine), were recently synthesized and displayed more potent cytotoxicity than piplartine in different cancer cells, regulated RNA transcripts of several apoptosis-related genes, and induced reactive oxygen species (ROS)-mediated apoptosis in human colon carcinoma HCT116 cells. The present work aimed to explore the underlying mechanisms through which these ruthenium complexes induce cell death in HCT116 cells , as well as their action in a xenograft model. Both complexes significantly increased the percentage of apoptotic HCT116 cells, and co-treatment with inhibitors of JNK/SAPK, p38 MAPK, and MEK, which inhibits the activation of ERK1/2, significantly reduced the apoptosis rate induced by these complexes. Moreover, significant increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182), and phospho-ERK1 (T202/Y204) expressions were observed in cells treated with these complexes, indicating MAPK-mediated apoptosis. In addition, co-treatment with a p53 inhibitor (cyclic pifithrin-α) and the ruthenium complexes significantly reduced the apoptosis rate in HCT116 cells, and increased phospho-p53 (S15) and phospho-histone H2AX (S139) expressions, indicating induction of DNA damage and p53-dependent apoptosis. Both complexes also reduced HCT116 cell growth in a xenograft model. Tumor mass inhibition rates were 35.06, 29.71, and 32.03% for the complex (15 μmol/kg/day), complex (15 μmol/kg/day), and piplartine (60 μmol/kg/day), respectively. These data indicate these ruthenium complexes as new anti-colon cancer drugs candidates.
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http://dx.doi.org/10.3389/fonc.2019.00582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616125PMC
July 2019

In vitro and in vivo anti-leukemia activity of the stem bark of Salacia impressifolia (Miers) A. C. Smith (Celastraceae).

J Ethnopharmacol 2019 Mar 13;231:516-524. Epub 2018 Nov 13.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia 40296-710, Brazil. Electronic address:

Ethnopharmacological Relevance: Salacia impressifolia (Miers) A. C. Smith (family Celastraceae) is a traditional medicinal plant found in the Amazon Rainforest known as "miraruíra", "cipó-miraruíra" or "panu" and is traditionally used to treat dengue, flu, inflammation, pain, diabetes, male impotency, renal affections, rheumatism and cancer.

Aim Of The Study: The aim of this study was to investigate in vitro and in vivo anti-leukemia activity of the stem bark of S. impressifolia in experimental models.

Materials And Methods: The in vitro cytotoxic activity of extracts, fractions and quinonemethide triterpenes (22-hydroxytingenone, tingenone and pristimerin) from the stem bark of S. impressifolia in cultured cancer cells was determined. The in vivo antitumor activity of the ethyl acetate extract (EAE) and of its fraction (FEAE.3) from the stem bark of S. impressifolia was assessed in C.B-17 severe combined immunodeficient (SCID) mice engrafted with human promyelocytic leukemia HL-60 cells.

Results: The extract EAE, its fraction FEAE.3, and quinonemethide triterpenes exhibited potent cytotoxicity against cancer cell lines, including in vitro anti-leukemia activity against HL-60 and K-562 cells. Moreover, extract EAE and its fraction FEAE.3 inhibited the in vivo development of HL-60 cells engrafted in C.B-17 SCID mice. Tumor mass inhibition rates were measured as 40.4% and 81.5% for the extract EAE (20 mg/kg) and for its fraction FEAE.3 (20 mg/kg), respectively.

Conclusions: Ethyl acetate extract and its fraction from the stem bark of S. impressifolia exhibit in vitro and in vivo anti-leukemia activity that can be attributed to their quinonemethide triterpenes. These data confirm the ethnopharmacological use of this species and may contribute to the development of a novel anticancer herbal medicine.
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http://dx.doi.org/10.1016/j.jep.2018.11.008DOI Listing
March 2019

A novel ruthenium complex with xanthoxylin induces S-phase arrest and causes ERK1/2-mediated apoptosis in HepG2 cells through a p53-independent pathway.

Cell Death Dis 2018 01 23;9(2):79. Epub 2018 Jan 23.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.

Ruthenium-based compounds have gained great interest due to their potent cytotoxicity in cancer cells; however, much of their potential applications remain unexplored. In this paper, we report the synthesis of a novel ruthenium complex with xanthoxylin (RCX) and the investigation of its cellular and molecular action in human hepatocellular carcinoma HepG2 cells. We found that RCX exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures and in a 3D model of multicellular cancer spheroids formed from HepG2 cells. This compound is detected at a high concentration in the cell nuclei, induces DNA intercalation and inhibits DNA synthesis, arresting the cell cycle in the S-phase, which is followed by the activation of the caspase-mediated apoptosis pathway in HepG2 cells. Gene expression analysis revealed changes in the expression of genes related to cell cycle control, apoptosis and the MAPK pathway. In addition, RCX induced the phosphorylation of ERK1/2, and pretreatment with U-0126, an MEK inhibitor known to inhibit the activation of ERK1/2, prevented RCX-induced apoptosis. In contrast, pretreatment with a p53 inhibitor (cyclic pifithrin-α) did not prevent RCX-induced apoptosis, indicating the activation of a p53-independent apoptosis pathway. RCX also presented a potent in vivo antitumor effect in C.B-17 SCID mice engrafted with HepG2 cells. Altogether, these results indicate that RCX is a novel anticancer drug candidate.
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http://dx.doi.org/10.1038/s41419-017-0104-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833756PMC
January 2018

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

Oncotarget 2017 Nov 1;8(61):104367-104392. Epub 2017 Nov 1.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.

Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF) (1) and [Ru(piplartine)(dppb)(bipy)](PF) (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway.
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http://dx.doi.org/10.18632/oncotarget.22248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732813PMC
November 2017

Antitumour Activity of the Microencapsulation of Annona vepretorum Essential Oil.

Basic Clin Pharmacol Toxicol 2016 Mar 6;118(3):208-13. Epub 2015 Oct 6.

Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (CPqGM-FIOCRUZ/BA), Salvador, Brazil.

Annona vepretorum Mart. (Annonaceae), popularly known as 'bruteira', has nutritional and medicinal uses. This study investigated the chemical composition and antitumour potential of the essential oil of A. vepretorum leaf alone and complexed with β-cyclodextrin in a microencapsulation. The essential oil was obtained by hydrodistillation using a Clevenger-type apparatus and analysed using GC-MS and GC-FID. In vitro cytotoxicity of the essential oil and some of its major constituents in tumour cell lines from different histotypes was evaluated using the alamar blue assay. Furthermore, the in vivo efficacy of essential oil was demonstrated in mice inoculated with B16-F10 mouse melanoma. The essential oil included bicyclogermacrene (35.71%), spathulenol (18.89%), (E)-β-ocimene (12.46%), α-phellandrene (8.08%), o-cymene (6.24%), germacrene D (3.27%) and α-pinene (2.18%) as major constituents. The essential oil and spathulenol exhibited promising cytotoxicity. In vivo tumour growth was inhibited by the treatment with the essential oil (inhibition of 34.46%). Importantly, microencapsulation of the essential oil increased in vivo tumour growth inhibition (inhibition of 62.66%).
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http://dx.doi.org/10.1111/bcpt.12488DOI Listing
March 2016

Antitumor Properties of the Essential Oil From the Leaves of Duguetia gardneriana.

Planta Med 2015 Jul 30;81(10):798-803. Epub 2015 Jun 30.

Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (Fiocruz), Salvador, Bahia, Brazil.

Duguetia gardneriana, popularly known in the Brazilian northeast as "jaquinha", is a species belonging to the family Annonaceae. The aim of this work was to assess the chemical composition and antitumor properties of the essential oil from the leaves of D. gardneriana in experimental models. The chemical composition of the essential oil was analyzed via gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. In vitro cytotoxic activity was determined in cultured tumor cells, and in vivo antitumor activity was assessed in B16-F10-bearing mice. The identified compounds were β-bisabolene (80.99%), elemicin (8.04%), germacrene D (4.15%), and cyperene (2.82%). The essential oil exhibited a cytotoxic effect, with IC50 values of 16.89, 19.16, 13.08, and 19.33 µg/mL being obtained for B16-F10, HepG2, HL-60, and K562 cell lines, respectively. On the other hand, β-bisabolene was inactive in all of the tested tumor cell lines (showing IC50 values greater than 25 µg/mL). The in vivo analysis revealed tumor growth inhibition rates of 5.37-37.52% at doses of 40 and 80 mg/kg/day, respectively. Herein, the essential oil from the leaves of D. gardneriana presented β-bisabolene as the major constituent and showed cytotoxic and antitumor potential.
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http://dx.doi.org/10.1055/s-0035-1546130DOI Listing
July 2015

Antitumor Properties of the leaf essential oil of Zornia brasiliensis.

Planta Med 2015 May 9;81(7):563-7. Epub 2015 Apr 9.

Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (Fiocruz), Salvador, Bahia, Brazil.

Zornia brasiliensis, popularly known as "urinária", "urinana", and "carrapicho", is a medicinal plant used in Brazilian northeast folk medicine as a diuretic and against venereal diseases. The aim of this study was to investigate the chemical composition and antitumor potential of the leaf essential oil of Z. brasiliensis. The essential oil was obtained by hydrodistillation using a Clevenger-type apparatus and analyzed by GC-MS and GC-FID. Its composition was characterized by the presence of trans-nerolidol, germacrene D, trans-caryophyllene, α-humulene, and farnesene as major constituents. In vitro cytotoxicity of the essential oil and some of its major constituents (trans-nerolidol, trans-caryophyllene, and α-humulene) was evaluated for tumor cell lines from different histotypes using the Alamar blue assay. The essential oil, but not the constituents tested, presented promising cytotoxicity. Furthermore, mice inoculated with B16-F10 mouse melanoma were used to confirm its in vivo effectiveness. An in vivo antitumor study showed tumor growth inhibition rates of 1.68-38.61 % (50 and 100 mg/kg, respectively). In conclusion, the leaf essential oil of Z. brasiliensis presents trans-nerolidol, germacrene D, trans-caryophyllene, α-humulene, and farnesene as major constituents and is able to inhibit cell proliferation in cultures as well as in tumor growth in mice.
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http://dx.doi.org/10.1055/s-0035-1545842DOI Listing
May 2015
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