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1.
Chem Biodivers ; 18(3): e2000938, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33508178

RESUMEN

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 IC50 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.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Lauraceae/química , Aceites Volátiles/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Ratones , Ratones SCID , Aceites Volátiles/química , Aceites Volátiles/aislamiento & purificación , Corteza de la Planta/química , Estereoisomerismo , Relación Estructura-Actividad
2.
Molecules ; 25(11)2020 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-32527068

RESUMEN

Cyperus articulatus 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, C. articulatus 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 IC50 values for cancer cell lines ranging from 28.5 µg/mL for HepG2 to >50 µg/mL for HCT116, and an IC50 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 G2/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 C. articulatus rhizome EO.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Cyperus/química , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Rizoma/química , Animales , Apoptosis , Neoplasias de la Mama/patología , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Ratones , Ratones SCID , Hojas de la Planta/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Cell Death Discov ; 10(1): 270, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38830859

RESUMEN

Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs.

4.
Biomed Pharmacother ; 177: 117059, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38955086

RESUMEN

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.


Asunto(s)
Apoptosis , Muerte Celular Autofágica , Neoplasias Hepáticas , Células Madre Neoplásicas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Células Hep G2 , Muerte Celular Autofágica/efectos de los fármacos , Tiazolidinas/farmacología , Animales , Ratones , Movimiento Celular/efectos de los fármacos , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química
5.
Biomolecules ; 12(5)2022 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-35625543

RESUMEN

Duguetia A. St. Hill (Annonaceae) is recognized as one of the major genera with approximately 100 species, 67 of which are found in Brazil (29 of those are endemic). They are arboreal species with edible fruits known as "pindaíba", "pindaíva" "pinha", and "envira" in Brazil. Many Duguetia species, in particular, have been used in traditional medicine to treat renal colic, stomachache, rheumatism, cough, toothache, muscle pain, fever, gastrointestinal pain, and breathing difficulties. In this study, we reviewed the chemical constituents and pharmacological properties of essential oils (EOs) from Duguetia species. A total of 12 species were found, along with their EO chemical constituents and bioactivities. Bicyclogermacrene, humulene epoxide II, spathulenol, germacrene D, caryophyllene oxide, viridiflorene, α-pinene, ß-caryophyllene, and ß-pinene were the main chemical constituents reported. The pharmacological effects of Duguetia species EOs included anti-inflammatory, antinociceptive, antibacterial, antifungal, antioxidant, anti-trypanosoma, cytotoxic and antitumor properties. This information adds to our understanding of the potential of the EOs of Duguetia species.


Asunto(s)
Annonaceae , Aceites Volátiles , Annonaceae/química , Antibacterianos/farmacología , Antifúngicos , Brasil , Aceites Volátiles/química , Aceites Volátiles/farmacología
6.
Biomolecules ; 12(11)2022 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-36358950

RESUMEN

Oxidative stress plays a central role in the pathophysiology of melanoma. Curcumin (CUR) is a polyphenolic phytochemical that stimulates reactive oxygen species (ROS) production, while disulfiram (DSS) is a US FDA-approved drug for the treatment of alcoholism that can act by inhibiting the intracellular antioxidant system. Therefore, we hypothesized that they act synergistically against melanoma cells. Herein, we aimed to study the antitumor potential of the combination of CUR with DSS in B16-F10 melanoma cells using in vitro and in vivo models. The cytotoxic effects of different combination ratios of CUR and DSS were evaluated using the Alamar Blue method, allowing the production of isobolograms. Apoptosis detection, DNA fragmentation, cell cycle distribution, and mitochondrial superoxide levels were quantified by flow cytometry. Tumor development in vivo was evaluated using C57BL/6 mice bearing B16-F10 cells. The combinations ratios of 1:2, 1:3, and 2:3 showed synergic effects. B16-F10 cells treated with these combinations showed improved apoptotic cell death and DNA fragmentation. Enhanced mitochondrial superoxide levels were observed at combination ratios of 1:2 and 1:3, indicating increased oxidative stress. In vivo tumor growth inhibition for CUR (20 mg/kg), DSS (60 mg/kg), and their combination were 17.0%, 19.8%, and 28.8%, respectively. This study provided data on the potential cytotoxic activity of the combination of CUR with DSS and may provide a useful tool for the development of a therapeutic combination against melanoma.


Asunto(s)
Antineoplásicos , Curcumina , Melanoma Experimental , Ratones , Animales , Curcumina/farmacología , Curcumina/uso terapéutico , Disulfiram/farmacología , Línea Celular Tumoral , Superóxidos/metabolismo , Ratones Endogámicos C57BL , Melanoma Experimental/metabolismo , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Estrés Oxidativo
7.
Biomed Pharmacother ; 129: 110402, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32574969

RESUMEN

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.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Aceites Volátiles/farmacología , Hojas de la Planta , Aceites de Plantas/farmacología , Plantaginaceae , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Femenino , Células HCT116 , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Células MCF-7 , Ratones SCID , Aceites Volátiles/aislamiento & purificación , Hojas de la Planta/química , Aceites de Plantas/aislamiento & purificación , Plantaginaceae/química , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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