Publications by authors named "Daniel P Bezerra"

66 Publications

Benzylated Dihydroflavones and Isoquinoline-Derived Alkaloids from the Bark of (Annonaceae) and Their Cytotoxicities.

Molecules 2021 Jun 18;26(12). Epub 2021 Jun 18.

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

R. E. Fries popularly known as "envira", is a species of the Annonaceae family endemic to Brazil. In our ongoing search for bioactive compounds from Annonaceae Amazon plants, the bark of was investigated by classical chromatography techniques that yielded thirteen compounds (alkaloids and flavonoids) described for the first time in as well as in the genus . The structure of these isolated compounds were established by extensive analysis using 1D/2D-NMR spectroscopy in combination with MS. The isolated alkaloids were identified as belonging to the subclasses: simple isoquinoline, thalifoline (); aporphine, anonaine (); oxoaporphine, liriodenine (); benzyltetrahydroisoquinolines, ()-(+)-reticuline (); dehydro-oxonorreticuline (3,4-dihydro-7-hydroxy-6-methoxy-1-isoquinolinyl)(3-hydroxy-4-methoxyphenyl)-methanone) (); (+)-1,2-reticuline -oxide (); and (+)-1,2-reticuline -oxide (); tetrahydroprotoberberine, coreximine (); and pavine, bisnorargemonine (). While the flavonoids belong to the benzylated dihydroflavones, isochamanetin (), dichamanetin (), and a mixture of uvarinol () and isouvarinol (). Compound is described for the first time in the literature as a natural product. The cytotoxic activity of the main isolated compounds was evaluated against cancer and non-cancerous cell lines. Among the tested compounds, the most promising results were found for the benzylated dihydroflavones dichamanetin (), and the mixture of uvarinol () and isouvarinol (), which presented moderate cytotoxic activity against the tested cancer cell lines (<20.0 µg·mL) and low cytotoxicity against the non-cancerous cell line MRC-5 (>25.0 µg·mL). Dichamanetin () showed cytotoxic activity against HL-60 and HCT116 with IC values of 15.78 µg·mL (33.70 µmol·L) and 18.99 µg·mL (40.56 µmol·L), respectively while the mixture of uvarinol () and isouvarinol () demonstrated cytotoxic activity against HL-60, with an IC value of 9.74 µg·mL, and HCT116, with an IC value of 17.31 µg·mL. These cytotoxic activities can be attributed to the presence of one or more hydroxybenzyl groups present in these molecules as well as the position in which these groups are linked. The cytotoxic activities of reticuline, anonaine and liriodenine have been previously established, with liriodenine being the most potent compound.
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http://dx.doi.org/10.3390/molecules26123714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235387PMC
June 2021

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

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

Biological and physical approaches on the role of piplartine (piperlongumine) in cancer.

Sci Rep 2020 12 17;10(1):22283. Epub 2020 Dec 17.

Department of Molecular Biology, School of Medicine of São José do Rio Preto (FAMERP), Av Brigadeiro Faria Lima 5416, São José do Rio Preto, SP, CEP 15090-000, Brazil.

Chronic inflammation provides a favorable microenvironment for tumorigenesis, which opens opportunities for targeting cancer development and progression. Piplartine (PL) is a biologically active alkaloid from long peppers that exhibits anti-inflammatory and antitumor activity. In the present study, we investigated the physical and chemical interactions of PL with anti-inflammatory compounds and their effects on cell proliferation and migration and on the gene expression of inflammatory mediators. Molecular docking data and physicochemical analysis suggested that PL shows potential interactions with a peptide of annexin A1 (ANXA1), an endogenous anti-inflammatory mediator with therapeutic potential in cancer. Treatment of neoplastic cells with PL alone or with annexin A1 mimic peptide reduced cell proliferation and viability and modulated the expression of MCP-1 chemokine, IL-8 cytokine and genes involved in inflammatory processes. The results also suggested an inhibitory effect of PL on tubulin expression. In addition, PL apparently had no influence on cell migration and invasion at the concentration tested. Considering the role of inflammation in the context of promoting tumor initiation, the present study shows the potential of piplartine as a therapeutic immunomodulator for cancer prevention and progression.
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http://dx.doi.org/10.1038/s41598-020-78220-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746756PMC
December 2020

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

Nucleobase Derivatives as Building Blocks to Form Ru(II)-Based Complexes with High Cytotoxicity.

ACS Omega 2020 Jan 3;5(1):122-130. Epub 2020 Jan 3.

Departamento de Química, Instituto de Ciências Exatas e Biológicas-Campus Morro do Cruzeiro, Universidade Federal de Ouro Preto-UFOP, CEP 35400-000 Ouro Preto, MG, Brazil.

Two new Ru(II)-based complexes containing 2-thiouracil derivatives, known as 2-thiouracil (2TU) and 6-methyl-2-thiouracil (6m2TU), were synthesized using [RuCl(PPh)(bipy)] as a precursor. The obtained compounds with a general formula [Ru(2TU)(PPh)(bipy)]PF () and [Ru(6m2TU)(PPh)(bipy)]PF () 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 is more promising than complex . Finally, the present study suggests that complexes and 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 G/G, G/M, and S phases.
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http://dx.doi.org/10.1021/acsomega.9b01921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963899PMC
January 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

Cranberry A-type proanthocyanidins selectively target acute myeloid leukemia cells.

Blood Adv 2019 11;3(21):3261-3265

Department of Medicine, Weill Cornell Medical College, New York, NY.

Most elderly patients affected with acute myeloid leukemia (AML) will relapse and die of their disease even after achieving complete remission, thus emphasizing the urgent need for new therapeutic approaches with minimum toxicity to normal hematopoietic cells. Cranberry (Vaccinium spp.) extracts have exhibited anticancer and chemopreventive properties that have been mostly attributed to A-type proanthocyanidin (A-PAC) compounds. A-PACs, isolated from a commercially available cranberry extract, were evaluated for their effects on leukemia cell lines, primary AML samples, and normal CD34+ cord blood specimens. Our results indicated potent and specific antileukemia activity in vitro. In addition, the antileukemia activity of A-PACs extended to malignant progenitor and stem cell populations, sparing their normal counterparts. The antileukemia effects of A-PACs were also observed in vivo using patient derived xenografts. Surprisingly, we found that the mechanism of cell death was driven by activation of NF-κB. Overall, our data suggest that A-PACs could be used to improve treatments for AML by targeting leukemia stem cells through a potentially novel pathway.
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http://dx.doi.org/10.1182/bloodadvances.2018026633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855100PMC
November 2019

Semi-synthesis of β-keto-1,2,3-triazole derivatives from ethinylestradiol and evaluation of the cytotoxic activity.

Heliyon 2019 Sep 6;5(9):e02408. Epub 2019 Sep 6.

Laboratório de Química Orgânica e Biocatálise, Instituto de Química de São Carlos, Universidade de São Paulo, Av. João Dagnone, 1100, Ed. Química Ambiental, Santa Angelina, São Carlos, SP, 13563-120, Brazil.

In this study, we report our contribution to the application of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction for the synthesis of β-keto-1,2,3-triazole derivatives from ethinylestradiol and their application in the inhibition of two human cancer cells lines: human breast adenocarcinoma (MCF-7) and human hepatocellular carcinoma (HepG2). The β-keto-1,2,3-triazole derivates exhibited moderate cytotoxic activity for the HepG2 cells with IC values of 29.7 μM (), 16.4 μM (), 17.8 μM (), 20.4 μM (), 28.1 μM () and 28.2 μM (). The semi-synthetic β-keto-1,2,3-triazoles derivatives were all characterized by FT-IR, NMR, HRMS and [α].
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http://dx.doi.org/10.1016/j.heliyon.2019.e02408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734327PMC
September 2019

Structure-Based Molecular Networking for the Target Discovery of Oxahomoaporphine and 8-Oxohomoaporphine Alkaloids from .

J Nat Prod 2019 08 12;82(8):2220-2228. Epub 2019 Aug 12.

Metabolomics and Mass Spectrometry Research Group , Amazonas State University , Manaus 690065-130 , Brazil.

In addition to seven known alkaloids (, -) and 1,2,4-trimethoxybenzene (), three isoquinoline-derived alkaloids (-), namely, duguetinine (), a compound based on an unprecedented oxahomoaporphine scaffold, and two new 8-oxohomoaporphine alkaloids, duguesuramine () and 11-methoxyduguesuramine (), and a new asarone-derived phenylpropanoid () were isolated from the bark of . The isolation workflow was guided by HPLC-HRESIMS/MS and molecular networking-based analyses. Twenty-four known alkaloids were dereplicated from the alkaloid-rich fraction network and were assigned by manual MS/MS interpretation. Their cytotoxic potential was evaluated.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00287DOI Listing
August 2019

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

Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.

J Inorg Biochem 2019 09 9;198:110751. Epub 2019 Jun 9.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luiz, KM 235 CP 676, CEP 13561-901 São Carlos, SP, Brazil; Instituto de Química, Universidade Federal de Goiás - UFG, CEP 74690-900 Goiânia, GO, Brazil. Electronic address:

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh)(2TU)] (1), [Ru(PPh)(6m2TU)] (2), [Ru(dppb)(2TU)] (3) and [Ru(dppb)(6m2TU)] (4), where PPh = 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 × 10 M. 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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http://dx.doi.org/10.1016/j.jinorgbio.2019.110751DOI Listing
September 2019

p-Cymene attenuates cancer pain via inhibitory pathways and modulation of calcium currents.

Phytomedicine 2019 Aug 17;61:152836. Epub 2019 Jan 17.

Department of Health Education, Federal University of Sergipe, Padre Álvares Pitangueira street, nº 248, Downtown, 49400-000 Lagarto, Sergipe, Brazil. Electronic address:

Background: Oncological pain is one of the most prevalent and difficult-to-treat symptoms in patients with cancer. p-Cymene (PC) is a monoterpene found in more than 100 different plant species, endowed with various pharmacological properties-particularly antinociceptive.

Hypothesis/purpose: PC has antinociceptive effect in a model of oncologic pain due to the activation of the descending inhibitory pathway of pain.

Study Design: A pre-clinical, longitudinal, blind and randomized study.

Methods: Male Swiss mice were induced with S180 cells in the right hind paw, then treated daily with PC (12.5, 25 and 50 mg/kg, s.c.) and screened for mechanical hyperalgesia, spontaneous nociception, nociception induced by non-noxious palpation, tumor growth, changes in the neuromuscular function and existence of bone degradation in the tumor area. The effect of PC on Ca currents (electrophysiological records), histological and neurochemical changes (immunofluorescence for Fos) were also evaluated.

Results: PC reduced (p < 0.05) the mechanical hyperalgesia, the spontaneous (p < 0.001) and non-noxious palpation (p < 0.001) nociceptions, not changing the tumor development, neuromuscular function or histopathological aspects of the paw affected. PC reduced Fos expression in the spinal cord (p < 0.001) and increased this expression in the PAG (p < 0.05) and in the NRM (p < 0.01). PC decreased the density of calcium channel currents (p < 0.05).

Conclusion: These results suggest the antinociceptive effect of PC on oncologic pain, probably acting in both ascending and descending pain pathways, and modulating the calcium channel currents in order to exert its effects.
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http://dx.doi.org/10.1016/j.phymed.2019.152836DOI Listing
August 2019

Carvacrol/β-cyclodextrin inclusion complex inhibits cell proliferation and migration of prostate cancer cells.

Food Chem Toxicol 2019 Mar 4;125:198-209. Epub 2019 Jan 4.

Department of Pharmacy, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil. Electronic address:

Carvacrol, a phenolic monoterpene derived from thyme oil has gained wide interest recently because of its anticancer activities. To improve the solubility of carvacrol, the formation of inclusion complexes with β-cyclodextrin was performed by ultrasound and freeze-drying methods and characterized using thermal analysis, FTIR, XRD, SEM, NMR and HPLC analysis. From these results, carvacrol was successfully complexed within β-cyclodextrin cavity. Moreover, HPLC analysis demonstrated a higher entrapment efficiency for freeze-drying method (81.20 ± 0.52%) in contrast to ultrasound method (34.02 ± 0.67%). Hence, freeze-drying inclusion complex was evaluated for its antiproliferative effect and cytotoxicity against prostate cancer cell line (PC3) in vitro. Further, freeze-drying complex led to a dose-dependent inhibition in tumor cell growth in 2D and 3D cell culture systems. Altogether, the inclusion of carvacrol in β-cyclodextrin led to the formation of stable complexes with potent antiproliferative effects against PC3 cells, in vitro. Such an improved cytotoxic effect can be attributed to the enhanced the aqueous solubility and bioavailability of carvacrol by effective complexation in β-cyclodextrin.
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http://dx.doi.org/10.1016/j.fct.2019.01.003DOI Listing
March 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

Antitumor Effect of the Essential Oil from the Leaves of Aubl. (Euphorbiaceae).

Molecules 2018 Nov 14;23(11). Epub 2018 Nov 14.

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

Aubl. (synonym Jabl.), popularly known as "orelha de burro", "maravuvuia", and/or "sangrad'água", is a medicinal plant used in Brazilian folk medicine as a depurative and in the treatment of infections, fractures, and colds. In this work, we investigated the chemical composition and in vitro cytotoxic and in vivo antitumor effects of the essential oil (EO) from the leaves of collected from the Amazon rainforest. The 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. In vitro cytotoxicity of the EO was assessed in cancer cell lines (MCF-7, HCT116, HepG2, and HL-60) and the non-cancer cell line (MRC-5) using the Alamar blue assay. Furthermore, annexin V-FITC/PI staining and the cell cycle distribution were evaluated with EO-treated HepG2 cells by flow cytometry. In vivo efficacy of the EO (40 and 80 mg/kg/day) was demonstrated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The EO included β-caryophyllene, thunbergol, cembrene, -cymene, and β-elemene as major constituents. The EO exhibited promising cytotoxicity and was able to cause phosphatidylserine externalization and DNA fragmentation without loss of the cell membrane integrity in HepG2 cells. In vivo tumor mass inhibition rates of the EO were 34.6% to 55.9%. Altogether, these data indicate the anticancer potential effect of .
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http://dx.doi.org/10.3390/molecules23112974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278459PMC
November 2018

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells.

Redox Biol 2019 01 12;20:182-194. Epub 2018 Oct 12.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador, Bahia, Brazil. Electronic address:

Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh)]PF (where, PIP-OH = piplartine demethylated derivative; and PPh = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.
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http://dx.doi.org/10.1016/j.redox.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198128PMC
January 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

Melipona mondury produces a geopropolis with antioxidant, antibacterial and antiproliferative activities.

An Acad Bras Cienc 2017 20;89(3 Suppl):2247-2259. Epub 2017 Jul 20.

Departamento de Ciências Biológicas, Universidade Estadual do Sudoeste da Bahia, Rua José Moreira Sobrinho, s/n, Jequiezinho, 45208-091 Jequié, BA, Brazil.

Geopropolis is a special type of propolis produced by stingless bees. Several pharmacological properties have been described for different types of geopropolis, but there have been no previous studies of the geopropolis from Melipona mondury. In this study, we investigated the antioxidant, antibacterial, and antiproliferative activities of M. mondury geopropolis, and determined its chemical profile. The antioxidant activity was determined using in vitro ABTS·+, ·DPPH, and β-carotene/linoleic acid co-oxidation methods. The antibacterial activity was determined using a microdilution method with Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant S. aureus. The antiproliferative effect was determined in tumor cell lines using the Alamar Blue assay. The chemical profile was obtained using UHPLC-MS and UHPLC-MS/MS. The butanolic fraction had the highest concentration of phenolic compounds and more potent antioxidant properties in all assays. This fraction also had bacteriostatic and bactericidal effects against all bacterial strains at low concentrations, especially S. aureus. The hexane fraction had the highest antiproliferative potential, with IC50 values ranging from 24.2 to 46.6 µg/mL in HL-60 (human promyelocytic leukemia cell) and K562 (human chronic myelocytic leukemia cell), respectively. Preliminary chemical analysis indicates the presence of terpenes and gallic acid in the geopropolis. Our results indicate the therapeutic potential of geopropolis from M. mondury against inflammatory, oxidative, infectious, and neoplastic diseases.
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http://dx.doi.org/10.1590/0001-3765201720160725DOI Listing
May 2018

Physico-chemical characterization and antibacterial activity of inclusion complexes of Hyptis martiusii Benth essential oil in β-cyclodextrin.

Biomed Pharmacother 2017 May 20;89:201-207. Epub 2017 Feb 20.

Department of Biological Chemistry, Regional University of Cariri, Crato, Ceará, Brazil. Electronic address:

Cyclodextrins (CDs) have been used as important pharmaceutical excipients for improve the physicochemical properties of the drugs of low solubility as the essential oil of Hyptis martiusii. This oil is important therapeutically, but the low solubility and bioavailability compromises your use. Therein, the aim of this study was to obtain and to characterize physico-chemically the samples obtained by physical mixture (PM), paste complexation (PC) and slurry complexation (SC) of the essential oil Hyptis martiusii (EOHM) in β-CD, and to compare the antibacterial and modulatory-antibiotic activity of products obtained and oil free. The physicochemical characterization was performed by differential scanning calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Karl Fischer titration. Additionally, the antibacterial tests were performed by microdilution technique. Thus, it was observed that the PM method showed low complexing capacity, unlike PC and SC in which it was observed the formation of inclusion complexes. In addition, the second stage of the TG/DTG curves showed that SC was the best method inclusion with mass loss of 6.9% over the PC that was 6.0%. The XRD results corroborate with the results above suggesting the formation of new solid phase and the SEM photomicrographs showed the porous surface of the samples PC and SC. The essential oil alone demonstrated an antibacterial and modulatory effect against the S. aureus and the Gram negative strain, respectively. However, the β-CD and the inclusion complex did not demonstrate any biological activity in the performed antibacterial assays.
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http://dx.doi.org/10.1016/j.biopha.2017.01.158DOI Listing
May 2017

Pyranochromones from Dictyoloma vandellianum A. Juss and Their Cytotoxic Evaluation.

Chem Biodivers 2017 Mar 16;14(3). Epub 2017 Feb 16.

Institute of Chemistry, Federal University of Bahia, Barão do Jeremoabo 147, Ondina, 40170-115, Salvador, BA, Brazil.

One new chromone 3,3-dimethylallylspatheliachromene methyl ether (1), as well as five known chromones, 6-(3-methylbut-2-enyl) allopteroxylin methyl ether (2), 6-(3-methylbut-2-enyl) allopteroxylin (3), 3,3-dimethylallylspatheliachromene (4), 5-O-methylcneorumchromone K (5) and spatheliabischromene (6), two alkaloids, 8-methoxy-N-methylflindersine (7) and 8-methoxyflindersine (8), and two limonoids, limonin diosphenol (9) and rutaevin (10), were isolated from Dictyoloma vandellianum A. Juss (Rutaceae). Cytotoxic activities towards tumor cell lines B16-F10, HepG2, K562 and HL60 and non-tumor cells PBMC were evaluated for compounds 1 - 6. Compound 1 was the most active showing IC values ranging from 6.26 to 14.82 μg/ml in B16-F10 and K562 cell lines, respectively, and presented IC value of 11.65 μg/ml in PBMC cell line.
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http://dx.doi.org/10.1002/cbdv.201600276DOI Listing
March 2017

Cytotoxic Alkaloids from the Stem of Xylopia laevigata.

Molecules 2016 Jul 8;21(7). Epub 2016 Jul 8.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ), Salvador 40000-000, Bahia, Brazil.

Xylopia laevigata (Annonaceae), known locally as "meiú" or "pindaíba", is widely used in folk medicine in Northeastern Brazil. In the present work, we performed phytochemical analyses of the stem of X. laevigata, which led to the isolation of 19 alkaloids: (-)-roemerine, (+)-anonaine, lanuginosine, (+)-glaucine, (+)-xylopine, oxoglaucine, (+)-norglaucine, asimilobine, (-)-xylopinine, (+)-norpurpureine, (+)-N-methyllaurotetanine, (+)-norpredicentrine, (+)-discretine, (+)-calycinine, (+)-laurotetanine, (+)-reticuline, (-)-corytenchine, (+)-discretamine and (+)-flavinantine. The in vitro cytotoxic activity toward the tumor cell lines B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), K562 (human chronic myelocytic leukemia) and HL-60 (human promyelocytic leukemia) and non-tumor peripheral blood mononuclear cells (PBMCs) was tested using the Alamar Blue assay. Lanuginosine, (+)-xylopine and (+)-norglaucine had the highest cytotoxic activity. Additionally, the pro-apoptotic effects of lanuginosine and (+)-xylopine were investigated in HepG2 cells using light and fluorescence microscopies and flow cytometry-based assays. Cell morphology consistent with apoptosis and a marked phosphatidylserine externalization were observed in lanuginosine- and (+)-xylopine-treated cells, suggesting induction of apoptotic cell death. In addition, (+)-xylopine treatment caused G₂/M cell cycle arrest in HepG2 cells. These data suggest that X. laevigata is a potential source for cytotoxic alkaloids.
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http://dx.doi.org/10.3390/molecules21070890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273342PMC
July 2016
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