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1.
PLoS One ; 15(9): e0239614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986753

RESUMO

Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice. The mice were exposed to one of nine cytotoxic anticancer drugs (5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine) to assess the correlation between chemosensitivity response and variant allele frequency. We found 162 candidate variants that were possibly associated with chemosensitivity to one or more of the nine anticancer drugs (P < 0.01). In a subgroup analysis of breast and gastric cancer xenografts, 78 and 67 variants, respectively, were possibly associated with chemosensitivity. This approach may help to contribute to the development of personalized treatments that may allow for the prescription of optimal chemotherapy regimens among patients with cancer.


Assuntos
Antineoplásicos/uso terapêutico , Citotoxinas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Variação Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Resultado do Tratamento , Sequenciamento Completo do Exoma
2.
Acta Crystallogr C Struct Chem ; 76(Pt 8): 723-733, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32756034

RESUMO

The present study examines a series of six biologically-active flavonoid and chromanone derivatives by X-ray crystal structure analysis: (E)-3-benzylidene-2-phenylchroman-4-one, C22H16O2, I, (E)-3-(4-methylbenzylidene)-2-phenylchroman-4-one, C23H18O2, II, (E)-3-(3-methylbenzylidene)-2-phenylchroman-4-one, C23H18O2, III, (E)-3-(4-methoxybenzylidene)-2-phenylchroman-4-one, C23H18O3, IV, (E)-3-benzylidenechroman-4-one, C16H12O2, V, and (E)-3-(4-methoxybenzylidene)chroman-4-one, C17H14O3, VI. The cytotoxic activities of the presented crystal structures have been determined, together with their intermolecular interaction preferences and Hirshfeld surface characteristics. An inverse relationship was found between the contribution of C...C close contacts to the Hirshfeld surface and cytotoxic activity against the WM-115 cancer line. Dependence was also observed between the logP value and the percentage contribution of C...H contacts to the Hirshfeld surface.


Assuntos
Antineoplásicos/farmacologia , Cromanos/química , Citotoxinas/farmacologia , Flavonoides/química , Antineoplásicos/química , Cristalografia por Raios X , Citotoxinas/química , Ligação de Hidrogênio
3.
Arch Biochem Biophys ; 692: 108546, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32818507

RESUMO

Epigallocatechin-3-gallate (EGCG), a major polyphenol component of green tea, presents anticancer efficacy. However, its exact mechanism of action is not known. In this study, we evaluated the effect of EGCG alone or in combination with current chemotherapeutics [gemcitabine, 5-flourouracil (5-FU), and doxorubicin] on pancreatic, colon, and lung cancer cell growth, as well as the mechanisms involved in the combined action. EGCG reduced pancreatic, colon, and lung cancer cell growth in a concentration and time-dependent manner. EGCG strongly induced apoptosis and blocked cell cycle progression. Moreover, EGCG enhanced the growth inhibitory effect of 5-FU and doxorubicin. Of note, EGCG enhanced 5-FU's and doxorubicin's effect on apoptosis, but not on cell cycle. Mechanistically, EGCG reduced ERK phosphorylation concentration-dependently, and sensitized gemcitabine, 5-FU, and doxorubicin to further suppress ERK phosphorylation in multiple cancer cell lines. In conclusion, EGCG presents a strong anticancer effect in pancreatic, colon, and lung cancer cells and is a robust combination partner for multiple chemotherapeutics as evidenced by reducing cancer cell growth, in part, by inhibiting the ERK pathway.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Catequina/análogos & derivados , Citotoxinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células A549 , Catequina/farmacologia , Células HT29 , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
4.
PLoS One ; 15(7): e0236319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726328

RESUMO

Jacaranda mimosifolia trees are grown in frost-free regions globally. The aim of this study was to evaluate the methanol crude extract and various fractions of increasing polarity of J. mimosifolia leaves for bioactive metabolites, as well as antimicrobial, antioxidant and anticancer activities. The anti-inflammatory potential of the various fractions of J. mimosifolia leaf extract was studied via the lipoxygenase (LOX) inhibitory assay. Methanol crude extract (ME), derived fractions extracted with chloroform (CF) and ethyl acetate (EAF), and residual aqueous extract (AE) of dried J. mimosifolia leaves were assayed for polyphenolic compounds, their antioxidant, antimicrobial and lipoxygenase (LOX) inhibitory activities, and anticancer properties. Polyphenolic compounds were determined via HPLC while phytochemicals (total phenolics, flavonoids, tannins and ortho-diphenol contents), antioxidant activities (DPPH, hydrogen peroxideperoxide, hydroxyl and superoxide radical anions) and LOX were measured via spectrophotometry. Methanol extracts and various fractions were evaluated for antibacterial activities against Bacillus subtilis, Klebsiella pneumonia, Pseudomonas aeruginosa and Staphylococcus aureus. Antifungal potential of the fractions was tested against three species: Aspergillus flavus, Aspergillus fumigatus and Fusarium oxysporum. The highest values for total phenolic content (TPC), total flavonoid content (TFC), flavonols, tannins and ortho-diphenols were in the ME, followed by CF > EAF > AE. ME also had the highest antioxidant activity with EC50 values 48±1.3, 45±2.4, 42±1.3 and 46±1.3 µg/mL based on the DPPH, hydrogen peroxide, hydroxyl radical and superoxide radical assays, respectively. TPC and TFC showed a significant, strong and positive correlation with the values for each of these antioxidant activities. ME exhibited anti-inflammatory potential based on its LOX inhibitory activity (IC50 = 1.3 µg/mL). ME also had the maximum antibacterial and antifungal potential, followed by EAF > CF > AE. Furthermore, ME showed the strongest cytotoxic effect (EC50 = 10.7 and 17.3 µg/mL) against human hormone-dependent prostate carcinoma (LnCaP) and human lung carcinoma (LU-1) cell lines, respectively. Bioactive compounds present in leaf methanol extracts of J. mimosifolia were identified using gas chromatography-mass spectrometry (GC-MS). Fifteen compounds were identified including phenolic and alcoholic compounds, as well as fatty acids. Our results suggest that J. mimosifolia leaves are a good source of natural products with antioxidant, anti-inflammatory and anti-cancer properties for potential therapeutic, nutraceutical and functional food applications.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Bignoniaceae/química , Extratos Vegetais/farmacologia , Anti-Infecciosos/química , Antioxidantes/química , Aspergillus/efeitos dos fármacos , Aspergillus/patogenicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Extratos Vegetais/química , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade
5.
Toxicol Appl Pharmacol ; 401: 115071, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454055

RESUMO

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ivermectina/análogos & derivados , Lactonas/farmacologia , Compostos Macrocíclicos/farmacologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Ivermectina/química , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
6.
Acta Crystallogr C Struct Chem ; 76(Pt 3): 269-275, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32132285

RESUMO

A new iridoid glycoside, methyl (3R,4R,4aS,7S,7aR)-3-hydroxy-7-methyl-5-oxooctahydrocyclopenta[c]pyran-4-carboxylate-3-O-ß-D-(1'S,2'R,3'S,4'S,5'R)-glucopyranoside, named loniceroside A, C17H26O10, (1), was obtained from the aerial parts of Lonicera saccata. Its structure was established based on an analysis of spectroscopic data, including 1D NMR, 2D NMR and HRESIMS, and the configurations of the chiral C atoms were determined by X-ray crystallographic analysis. The single-crystal structure reveals that the cyclopenta[c]pyran scaffold is formed from a five-membered ring and a chair-like six-membered ring connected through two bridgehead chiral C atoms. In the solid state, the glucose group of (1) plays an important role in constructing an unusual supramolecular motif. The structure analysis revealed adjacent molecules linked together through intermolecular O-H...O hydrogen bonds to generate a banded structure. Furthermore, the banded structures are linked into a three-dimensional network by interesting hydrogen bonds. Biogenetically, compound (1) carries a glucopyranosyloxy moiety at the C-3 position, representing a rare structural feature for naturally occurring iridoid glycosides. The growth inhibitory effects against human cervical carcinoma cells (Hela), human lung adenocarcinoma cells (A549), human acute mononuclear granulocyte leukaemia (THP-1) and the human liver hepatocellular carcinoma cell line (HepG2) were evaluated by the MTT method.


Assuntos
Citotoxinas/farmacologia , Glicosídeos Iridoides/farmacologia , Lonicera/química , Cristalografia por Raios X , Citotoxinas/isolamento & purificação , Humanos , Ligação de Hidrogênio , Glicosídeos Iridoides/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular
7.
BMC Complement Med Ther ; 20(1): 8, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32020891

RESUMO

BACKGROUND: The proliferation and resistance of microorganisms area serious threat against humankind and the search for new therapeutics is needed. The present report describes the antiplasmodial and anticancer activities of samples isolated from the methanol extract of Albizia zygia (Mimosaseae). MATERIAL: The plant extract was prepared by maceration in methanol. Standard chromatographic, HPLC and spectroscopic methods were used to isolate and identify six compounds (1-6). The acetylated derivatives (7-10) were prepared by modifying 2-O-ß-D-glucopyranosyl-4-hydroxyphenylacetic acid and quercetin 3-O-α-L-rhamnopyranoside, previously isolated from A. zygia (Mimosaceae). A two-fold serial micro-dilution method was used to determine the IC50s against five tumor cell lines and Plasmodium falciparum. RESULTS: In general, compounds showed moderate activity against the human pancreatic carcinoma cell line MiaPaca-2 (10 < IC50 < 20 µM) and weak activity against other tumor cell lines such as lung (A-549), hepatocarcinoma (HepG2) and human breast adenocarcinoma (MCF-7and A2058) (IC50 > 20 µM). Additionally, the two semi-synthetic derivatives of quercetin 3-O-α-L-rhamnopyranoside exhibited significant activity against P. falciparum with IC50 of 7.47 ± 0.25 µM for compound 9 and 6.77 ± 0.25 µM for compound 10, higher than that of their natural precursor (IC50 25.1 ± 0.25 µM). CONCLUSION: The results of this study clearly suggest that, the appropriate introduction of acetyl groups into some flavonoids could lead to more useful derivatives for the development of an antiplasmodial agent.


Assuntos
Albizzia/química , Antimaláricos/farmacologia , Citotoxinas/farmacologia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Camarões , Linhagem Celular Tumoral , Cromatografia Líquida , Humanos , Espectrometria de Massas , Estrutura Molecular , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos
8.
J Mater Chem B ; 8(11): 2256-2268, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32100783

RESUMO

Amyloid ß-peptide (Aß) aggregation induced by metal ions such as Cu2+ has been recognized as a crucial step in the pathogenesis of Alzheimer's disease (AD), so development of multifunctional agents that are able to inhibit Aß aggregation and modulate Cu2+-Aß species is considered as a promising strategy for fighting against AD. Our recent work proved that basification of human lysozyme (hLys) is in favor of enhancing the inhibition of Aß aggregation. Based on the finding, we have herein designed R-hLys, a conjugate of bifunctional alkaline decapeptide (RTHLVFFARK, RK10) coupled onto hLys via reaction with the carboxyl groups on hLys. The design created an even more basic protein than hLys, thus increasing the potency of hLys on inhibiting Aß fibrillation. Moreover, the RK10 conjugation onto hLys introduced a specific Cu2+-chelator and an additional peptide inhibitor (LVFFARK). Thus, a multifunctional modulator on Cu2+-mediated Aß aggregation and cytotoxicity was developed. The multifunctional effects of R-hLys were systematically investigated on Aß aggregation, Cu2+-mediated Aß aggregation, ROS production, and remodeling mature Aß species by comparison to its counterparts. The results revealed the following: (1) R-hLys possesses high potency on inhibiting Aß fibrillogenesis; R-hLys at 1/5 to 1/4 of hLys concentration works similarly to hLys. (2) R-hLys exhibits high performance on inhibiting Cu2+-induced Aß aggregation and cytotoxicity; it increased the cell viability from 48.9% to 86.1% at an equimolar concentration to Aß. (3) R-hLys arrests the production of reactive oxygen species catalyzed by Cu2+ or Cu2+-Aß42 species. (4) R-hLys remodels mature Aß42 fibrils and Cu2+-Aß42 aggregates into small amorphous aggregates of lower cytotoxicity; by co-incubation with R-hLys, the cytotoxicities of mature Aß42 fibrils and Cu2+-Aß42 aggregates are reduced from 31.4% to 14.2% and 48.1% to 10.4%, respectively. Taken together, R-hLys is a potent multifunctional modulator for inhibiting Aß/Cu2+-mediated-Aß aggregation, suppressing ROS production and remodeling mature Aß42/Cu2+-Aß42 species.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Desenho de Fármacos , Muramidase/química , Peptídeos/química , Doença de Alzheimer/etiologia , Sequência de Aminoácidos , Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cobre/farmacologia , Citotoxinas/farmacologia , Humanos , Agregados Proteicos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
9.
Molecules ; 25(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075249

RESUMO

O-methylation of flavonoids is an important modification reaction that occurs in plants. O-methylation contributes to the structural diversity of flavonoids, which have several biological and pharmacological functions. In this study, an O-methyltransferase gene (CrOMT2) was isolated from the fruit peel of Citrus reticulata, which encoding a multifunctional O-methyltransferase and could effectively catalyze the methylation of 3'-, 5'-, and 7-OH of flavonoids with vicinal hydroxyl substitutions. Substrate preference assays indicated that this recombinant enzyme favored polymethoxylated flavones (PMF)-type substrates in vitro, thereby providing biochemical evidence for the potential role of the enzyme in plants. Additionally, the cytotoxicity of the methylated products from the enzymatic catalytic reaction was evaluated in vitro using human gastric cell lines SGC-7901 and BGC-823. The results showed that the in vitro cytotoxicity of the flavonoids with the unsaturated C2-C3 bond was increased after being methylated at position 3'. These combined results provide biochemical insight regarding CrOMT2 in vitro and indicate the in vitro cytotoxicity of the products methylated by its catalytic reaction.


Assuntos
Citrus/enzimologia , Citotoxinas/farmacologia , Flavonas/farmacologia , Proteínas de Plantas/química , Proteína O-Metiltransferase/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citrus/química , Citotoxinas/química , Citotoxinas/isolamento & purificação , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Flavonas/química , Flavonas/isolamento & purificação , Frutas/química , Frutas/enzimologia , Humanos , Concentração Inibidora 50 , Metilação , Proteínas de Plantas/isolamento & purificação , Proteína O-Metiltransferase/isolamento & purificação , Especificidade por Substrato
10.
Molecules ; 25(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075253

RESUMO

In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO- ligands belonging to adjacent chains were also detected that resemble the "base-pairing" assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms.


Assuntos
Apoptose/efeitos dos fármacos , Citotoxinas/farmacologia , Regulação Neoplásica da Expressão Gênica , Compostos Orgânicos de Estanho/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citotoxinas/síntese química , Desenho de Fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Compostos Orgânicos de Estanho/síntese química , Pirimidinas/síntese química , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
Molecules ; 25(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093264

RESUMO

Betulinic acid (BA) is a star member of the pentacyclic triterpenoid family, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, 21 BA-nitrogen heterocyclic derivatives were synthetized, in addition to four intermediates, 23 of which were first reported. Moreover, they were screened for in-vitro cytotoxicity against four tumor cell lines (Hela, HepG-2, BGC-823 and SK-SY5Y) by a standard methylthiazol tetrazolium (MTT) assay. The majority of these derivatives showed much stronger cytotoxic activity than BA. Remarkably, the most potent compound 7e (the half maximal inhibitory concentration (IC50) of which was 2.05 ± 0.66 µM) was 12-fold more toxic in vitro than BA-treated Hela. Furthermore, multiple fluorescent staining techniques and flow cytometry collectively revealed that compound 7e could induce the early apoptosis of Hela cells. Structure-activity relationships were also briefly discussed. The present study highlighted the importance of introducing nitrogen heterocyclic rings into betulinic acid in the discovery and development of novel antitumor agents.


Assuntos
Antineoplásicos , Citotoxinas , Neoplasias/tratamento farmacológico , Triterpenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade
12.
Molecules ; 25(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093423

RESUMO

Bersavine is the new bisbenzylisoquinoline alkaloid isolated from the Berberis vulgaris L.(Berberidaceae) plant. The results of cytotoxicity screening 48 h post-treatment showed thatbersavine considerably inhibits the proliferation and viability of leukemic (Jurkat, MOLT-4), colon(HT-29), cervix (HeLa) and breast (MCF-7) cancer cells with IC50 values ranging from 8.1 to 11 µM.The viability and proliferation of leukemic Jurkat and MOLT-4 cells were decreased after bersavinetreatment in a time- and dose-dependent manner. Bersavine manifested concentration-dependentantiproliferative activity in human lung, breast, ovarian and hepatocellular carcinoma cell linesusing a xCELLigence assay. Significantly higher percentages of MOLT-4 cells exposed to bersavineat 20 µM for 24 h were arrested in the G1 phase of the cell cycle using the flow cytometry method.The higher percentage of apoptotic cells was measured after 24 h of bersavine treatment. Theupregulation of p53 phosphorylated on Ser392 was detected during the progression of MOLT-4 cellapoptosis. Mechanistically, bersavine-induced apoptosis is an effect of increased activity ofcaspases, while reduced proliferation seems dependent on increased Chk1 Ser345 phosphorylationand decreased Rb Ser807/811 phosphorylation in human leukemic cells.


Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Berberis/química , Citotoxinas , Fase G1/efeitos dos fármacos , Leucemia/tratamento farmacológico , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Células HeLa , Células Hep G2 , Humanos , Células Jurkat , Leucemia/metabolismo , Leucemia/patologia , Células MCF-7
13.
Molecules ; 25(3)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033066

RESUMO

The incidence of gastrointestinal cancers is increasing every year. Irinotecan (CPT-11), a drug used in the treatment of colorectal cancer and gastric cancer, is metabolized by carboxylesterases to an active metabolite, SN-38, which is more cytotoxic. CAPE (caffeic acid phenethyl ester) is an active component of propolis, which has a high antibacterial, antiviral, and antineoplastic potential. This study analyses the impact of CAPE on the cytotoxic (MTT assay), genotoxic (comet assay) and proapoptotic (caspase-3/7 activity) potential of irinotecan and its metabolite SN-38 in cultures of gastrointestinal neoplastic cells (HCT116, HT29, AGS). Cytotoxicity and genotoxicity activities of these compounds were carried out in comparison with human peripheral blood lymphocytes (PBLs) in vitro. The antioxidant potential of CAPE was investigated in relation H2O2-induced oxidative stress in the both neoplastic cells and PBLs. CAPE expressed cytotoxic, genotoxic, and pro-apoptotic activity against AGS, HCT116, and HT29 tumor cells. CAPE, in the presence of different concentrations of irinotecan or SN38, decreased the cytotoxicity, genotoxicity, and pro-apoptotic activity in these cell lines, but it has no such action on normal human peripheral blood lymphocytes.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Irinotecano/farmacologia , Álcool Feniletílico/análogos & derivados , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/farmacologia , Dano ao DNA/efeitos dos fármacos , Sinergismo Farmacológico , Células HCT116 , Células HT29 , Humanos , Peróxido de Hidrogênio/toxicidade , Irinotecano/análogos & derivados , Linfócitos/efeitos dos fármacos , Mutagênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/farmacologia , Própole/farmacologia , Inibidores da Topoisomerase I/farmacologia
14.
Molecules ; 25(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013272

RESUMO

Searching for new bio-based herbicides is crucial for decreasing chemical pollution, protecting the environment, and sustaining biodiversity. Origanum vulgare is considered a promising source of essential oil with herbicidal effect. The mode of action is not known. The present study focused on (1) comparison of phytotoxic activity of Origanum vulgare EO on monocot (Triticum aestivum and Hordeum vulgare) and dicot species (Lepidium sativum and Sinapis alba); (2) and evaluating other antimicrobial biological activities against phytopatogen bacteria (Clavibacter michiganensis, Pseudomonas syringae pv. phaseolicola, Pseudomonas savastanoi, and Xanthomonas campestris); antifungal activity against Monilinia fructicola, Aspergillus niger, Penicillium expansum, and Botrytis cinerea; cytotoxic activity and antioxidant activity. According to the GC/MS analyses, the EO belongs to the thymol chemotype O. vulgare with its high content of thymol (76%). Germination of all four species was not influenced by EO. The phytotoxic effect was statistically significant in the monocot species, while in the dicot species the opposite was observed-a stimulation effect, which was also statistically significant. Strong biological activity of O. vulgare EO was noted on all phytopatogen bacteria and fungi in the highest dose. Cytotoxic activity showed an IC50 = 50.5 µg/mL. Antioxidant activity showed an IC50 = 106.6 µg/mL after 45 min experimental time. Based on the presented results, it is possible to conclude that thymol chemotype O. vulgare essential oil could be potentially used as a herbicide with selective effects on monocot plant species.


Assuntos
Herbicidas/farmacologia , Óleos Voláteis/farmacologia , Origanum/química , Óleos Vegetais/farmacologia , Plantas/efeitos dos fármacos , Timol/farmacologia , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Depuradores de Radicais Livres , Cromatografia Gasosa-Espectrometria de Massas , Herbicidas/isolamento & purificação , Hordeum/efeitos dos fármacos , Humanos , Lepidium sativum/efeitos dos fármacos , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Óleos Vegetais/química , Óleos Vegetais/isolamento & purificação , Sinapis/efeitos dos fármacos , Especificidade da Espécie , Timol/química , Timol/isolamento & purificação , Triticum/efeitos dos fármacos
15.
Toxicon ; 177: 25-34, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31982457

RESUMO

The use of preparations derived from frog skins for curative purposes antedates research history and is perpetuated in current medicine. The skins of anuran's (frogs and toads) are a rich source of compounds with a great importance in the search of antibiotics, analgesics, immunomodulators, enzymatic inhibitors and antitumoral agents applying to human health. Nowadays, cancer is the second most common cause of mortality with more than 8.2 million of deaths worldwide per year. Acute monocytic leukemia is the subtype M5 of acute myeloid leukemia (AML) a cancer type with reduced survival rates in patients. The monocyte to macrophage differentiation plays an essential role increasing the expansion of AML cell lines. Herein we studied the cytotoxic and antiproliferative activities of eleven amphibian species of three families belonging to Argentinean zones, against THP-1 monocytes and THP-1 macrophages acute monocytic leukemia cell lines. The evaluated species showed pronounced deleterious effects on acute monocytic leukemia THP-1 cell lines, reducing cell proliferation and inducing apoptosis, autophagy and in some cases cell aggregation. Being this work of great importance for the study of new natural anti-cancer compounds.


Assuntos
Venenos de Anfíbios/farmacologia , Anuros/fisiologia , Citotoxinas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Monocítica Aguda , Pele
16.
PLoS One ; 15(1): e0227926, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31951630

RESUMO

Cerium (Ce) oxide nanoparticles (CNP; nanoceria) are reported to have cytotoxic effects on certain cancerous cell lines, while at the same concentration they show no cytotoxicity on normal (healthy) cells. Redox-active CNP exhibit both selective prooxidative as well as antioxidative properties. The former is proposed to be responsible for impairment of tumor growth and invasion and the latter for rescuing normal cells from reactive oxygen species (ROS)-induced damage. Here we address possible underlying mechanisms of prooxidative effects of CNP in a metastatic human melanoma cell line. Malignant melanoma is the most aggressive form of skin cancer, and once it becomes metastatic the prognosis is very poor. We have shown earlier that CNP selectively kill A375 melanoma cells by increasing intracellular ROS levels, whose basic amount is significantly higher than in the normal (healthy) counterpart, the melanocytes. Here we show that CNP initiate a mitochondrial increase of ROS levels accompanied by an increase in mitochondrial thiol oxidation. Furthermore, we observed CNP-induced changes in mitochondrial bioenergetics, dynamics, and cristae morphology demonstrating mitochondrial dysfunction which finally led to tumor cell death. CNP-induced cell death is abolished by administration of PEG-conjugated catalase. Overall, we propose that cerium oxide nanoparticles mediate cell death via hydrogen peroxide production linked to mitochondrial dysfunction.


Assuntos
Cério/farmacologia , Citotoxinas/farmacologia , Melanoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Antioxidantes/química , Antioxidantes/farmacologia , Catalase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cério/química , Citotoxinas/química , Humanos , Melanoma/metabolismo , Melanoma/patologia , Mitocôndrias/patologia , Nanopartículas/química , Metástase Neoplásica , Compostos de Sulfidrila/metabolismo
17.
Exp Hematol ; 81: 32-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954171

RESUMO

Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on their synergism with the histone deacetylase inhibitor panobinostat (Pano) and the BCL2 inhibitor venetoclax/ABT199 was performed. Multiple myeloma cell lines MM.1R and MC/CAR were exposed to ∼IC20 levels of the drugs. Synergistic cytotoxicity was observed in cells exposed to the five-drug combination as indicated by combination indexes <1, supported by ∼86% inhibition of proliferation and ∼84% annexin V positivity in MM.1R and ∼58% inhibition of proliferation and ∼46% annexin V positivity in MC/CAR cells. Activation of the DNA damage response and apoptosis were suggested by a modest increase in the phosphorylation of ATM and its substrates; significant cleavage of PARP1, caspase 3, and heat shock protein 90; DNA fragmentation; mitochondrial membrane depolarization; and reactive oxygen species production. The five-drug combination significantly decreased the levels of PI3K, AKT, mTOR, RAPTOR, P-P70S6K, and eIF2α, with concomitant increases in P-AMPK and its substrate Tuberin/TSC2, suggesting that the mTOR signaling pathway was compromised. Endoplasmic reticulum stress through activation of the unfolded protein response was also observed as suggested by increases in the levels of calnexin, BiP/GRP78, ERO1-Lα, and protein disulfide isomerase, which may relate to venetoclax-mediated inhibition of BCL2 in the endoplasmic reticulum. This is the first report on the effects of a venetoclax-containing regimen on the unfolded protein response. These results provide a rationale to propose a clinical trial on use of Gem + Bu + Mel + Pano + Venetoclax as part of a conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mieloma Múltiplo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bussulfano/farmacologia , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melfalan/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Panobinostat/farmacologia , Sulfonamidas/farmacologia
18.
Chemosphere ; 247: 125819, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31927184

RESUMO

Brown tides were first observed in 2009 in the north-western Bohai Sea (Qinhuangdao sea area), China, and blooms have occurred at different scales in late spring every year since then. Although the detrimental effects on marine organisms of the causative phytoplankton species Aureococcus anophagefferens have been extensively studied, the mechanism remains poorly understood. We used erythrocytes and adrenal gland chromaffin tumor cells (PC12) to explore the hemolytic activity and cytotoxicity, respectively, of chloroform and methanol extracts of cultured A. anophagefferens isolated from the north-western Bohai Sea area. The methanol extracts showed no hemolytic or cytotoxic activity. Chloroform extracts had a potent hemolytic effect on rabbit erythrocytes; thin layer chromatography (TLC) indicated that the hemolysin was a kind of glycolipid compound. Erythrocyte lysis assay showed that erythrocytes of sea bream were sensitive to the hemolysin, whereas those of human and chicken erythrocytes were insensitive. The hemolytic effects were elevated as temperatures rose from 4 °C to 37 °C. Hemolytic blocking experiments showed that sphingomyelin and d-xylose can inhibit hemolysis significantly, while osmotic protectants with different hydrated molecular diameters had no inhibition, and the hemolysins had no obvious phospholipase activity. The chloroform extracts of A. anophagefferens had significant inhibitory effects on the viability of PC12 cells, and can induce efflux of lactic dehydrogenase (LDH) of PC12 cells and lead to their necrosis.


Assuntos
Citotoxinas/isolamento & purificação , Hemólise/efeitos dos fármacos , Fitoplâncton/citologia , Animais , Células Cultivadas , China , Citotoxinas/farmacologia , Eritrócitos/efeitos dos fármacos , Proteínas Hemolisinas/química , Proteínas Hemolisinas/isolamento & purificação , Proteínas Hemolisinas/farmacologia , Humanos , Células PC12 , Fitoplâncton/patogenicidade , Coelhos , Ratos , Estações do Ano , Estramenópilas/citologia , Estramenópilas/patogenicidade , Temperatura
19.
FASEB J ; 34(1): 1710-1727, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914660

RESUMO

Despite the importance of the tumor microenvironment in regulating tumor progression, few in vitro models have been developed to understand the effects of non-neoplastic cells and extracellular matrix (ECM) on drug resistance in glioblastoma (GBM) cells. Using CellTrace-labeled human GBM and microglial (MG) cells, we established a 2D co-culture including various ratios of the two cell types. Viability, proliferation, migration, and drug response assays were carried out to assess the role of MG. A 3D model was then established using a hyaluronic acid-gelatin hydrogel to culture a mixture of GBM and MG and evaluate drug resistance. A contact co-culture of fluorescently labeled GBM and MG demonstrated that MG cells modestly promoted tumor cell proliferation (17%-30% increase) and greater migration of GBM cells (>1.5-fold increase). Notably, the presence of MG elicited drug resistance even when in a low ratio (10%-20%) relative to co-cultured tumor cells. The protective effect of MG on GBM was greater in the 3D model (>100% survival of GBM when challenged with cytotoxics). This new 3D human model demonstrated the influence of non-neoplastic cells and matrix on chemoresistance of GBM cells to three agents with different mechanisms of action suggesting that such sophisticated in vitro approaches may facilitate improved preclinical testing.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Microglia/efeitos dos fármacos , Idoso , Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Glioblastoma/patologia , Humanos , Ácido Hialurônico/farmacologia , Hidrogéis/farmacologia , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Microambiente Tumoral/efeitos dos fármacos
20.
J Biochem Mol Toxicol ; 34(3): e22443, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31909879

RESUMO

The aim of this study was to evaluate the impact that 6-O-(3″, 4″-di-O-trans-cinnamoyl)-α- l-rhamnopyranosylcatalpol (Dicinn) and verbascoside (Verb), two compounds simultaneously reported in Verbascum ovalifolium, have on tumor cell viability, apoptosis, cell cycle kinetics, and intracellular reactive oxygen species (ROS) level. At 100 µg/mL and 48 hours incubation time, Dicinn and Verb produced good cytotoxic effects in A549, HT-29, and MCF-7 cells. Dicinn induced cell-cycle arrest at the G0 /G1 phase and apoptosis, whereas Verb increased the population of subG1 cells and cell apoptosis rates. Furthermore, the two compounds exhibited time-dependent ROS generating effects in tumor cells (1-24 hours). Importantly, no cytotoxic effects were induced in nontumor MCF-10A cells by the two compounds up to 100 µg/mL. Overall, the effects exhibited by Verb in tumor cells were more potent, which can be correlated with its structural features, such as the presence of phenolic hydroxyl groups.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Citotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Verbascum/química , Células A549 , Antineoplásicos Fitogênicos/química , Citotoxinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/patologia
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