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1.
Life Sci ; 243: 117271, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926243

RESUMO

AIMS: 1,8-Cineole is a plant-derived monoterpene and a major constituent of Eucalyptus essential oil. Previously, we demonstrated that 1,8-cineole inhibited hepatocellular carcinoma (HCC) HepG2 cell growth. However, the underlying mechanisms remain unknown. Here, we evaluated the mechanisms of action of 1,8-cineole and the potential benefits of its combination with anticancer compounds harboring "anti-senescence" properties in HepG2 cells. MAIN METHODS: Cell viability was determined by the MTT assay. Cell cycle was assessed through flow cytometry (FC) and western blot (WB). Senescence was determined by the SA-ß-galactosidase assay, and apoptosis by caspase-3 activity, WB, and TUNEL. MAPKs (ERK, JNK, and p38), AMPK, and Akt/mTOR were analyzed by WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were evaluated by FC and fluorescence microscopy. KEY FINDINGS: 1,8-Cineole inhibited cell proliferation by promoting G0/G1 arrest. While 1,8-cineole was unable to trigger apoptosis, it induced cellular senescence. 1,8-Cineole promoted ROS production, ΔΨm depolarization, AMPK, ERK, and p38 activation and mTOR inhibition. Antioxidants, like N-acetyl-L-cysteine and vitamins, prevented HepG2 cell growth inhibition and senescence induced by 1,8-cineole. Pre-incubation with 1,8-cineole sensitized HepG2 cells to the anti-senescence compounds, quercetin, simvastatin, U0126, and SB202190. Combinations of 1,8-cineole and each compound synergistically inhibited cell viability, and combined treatment with 1,8-cineole and simvastatin induced apoptosis. SIGNIFICANCE: 1,8-Cineole induces G0/G1 arrest and senescence in HepG2 cells through oxidative stress and MAPK, AMPK, and Akt/mTOR pathways, and sensitizes cells to anti-senescence drugs, suggesting that 1,8-cineole has potential as an antineoplastic and adjuvant compound in combination with anti-senescence drugs in HCC therapy.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Eucaliptol/farmacologia , Fase G1/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Antioxidantes/farmacologia , Relação Dose-Resposta a Droga , Indução Enzimática , Eucaliptol/administração & dosagem , Células Hep G2 , Humanos , Proteínas Quinases/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
2.
J Agric Food Chem ; 68(1): 213-224, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31861958

RESUMO

Asparanin A (AA), a steroidal saponin from Asparagus officinalis L., has anticancer activity: however, its detailed molecular mechanisms in endometrial cancer (EC) have not been studied so far. We evaluated the anticancer activity and underlying mechanism of AA on EC cell line Ishikawa in vitro and in vivo. AA inhibited the Ishikawa cell proliferation and caused cell morphology alteration and cell cycle arrest in G0/G1 phase. Moreover, it could induce apoptosis through mitochondrial pathway, including the deregulation of Bak/Bcl-xl ratio which led to the generation of ROS, up-regulation of cytochrome c followed by decrease of Δψm, and activation of caspases, besides inhibition of the PI3K/AKT/mTOR pathway. In vivo data showed that administration of AA significantly inhibited the tumor tissue cell proliferation, reduced the tumor growth, and induced the apoptosis occurrence. AA can be a possible functional food ingredient to cure endometrial cancer followed by clinical trials.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Asparagus (Planta)/química , Neoplasias do Endométrio/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocromos c/metabolismo , Neoplasias do Endométrio/fisiopatologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
3.
Ecotoxicol Environ Saf ; 187: 109851, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670181

RESUMO

Cadmium is a heavy metal pollutant that has been reported to cause oxidative stress, apoptosis, and autophagy in cells, while the flavone isoorientin is a traditional Chinese medicine extract that has proven antioxidant and anti-inflammatory properties. Accordingly, in this study we used the rat proximal tubular cell line NRK-52E and primary rat proximal tubular (rPT) cells as models to investigate the effects of isoorientin against Cadmium-induced cell injury and the mechanism of these effects. Comet assay, Western blot, flow cytometry, immunofluorescence, and transmission electron microscopy were used to evaluate cell damage and cell-cycle-related protein expression. Furthermore, real-time cell analysis, cell-counting kit-8, and ELISA were used to investigate the role of isoorientin in Cadmium-induced cell injury. The results revealed that treatment of rat renal tubular epithelial cells with 2.5 µM Cd for 12 h resulted in DNA damage and G0/G1 cell cycle arrest, while isoorientin attenuated this Cd-induced damage.


Assuntos
Antioxidantes/farmacologia , Cádmio/toxicidade , Dano ao DNA/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Luteolina/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos
4.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570442

RESUMO

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Mamárias Animais/metabolismo , Fosforilação/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Eur J Pharmacol ; 859: 172528, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31288004

RESUMO

ß-Cryptoxanthin has been associated with reduced-risk of some cancers. However, the mechanisms of ß-cryptoxanthin still remain unclearly understood in gastric cancer (GC). In this study, we examined the effect of ß-cryptoxanthin on AMPK signal in human gastric cancer cells. AGS and SGC-7901 cells were treated with ß-cryptoxanthin (0-40 µM) and AGS cells were injected in BALB/c (nu/nu) mice to analyze the effect of ß-cryptoxanthin on GC. We found that ß-cryptoxanthin induced inhibitory effect on the cell viability in a time- and concentration-dependent manner. The number of migrated cells and protein levels of matrix metalloproteinase (MMP) -2 and MMP-9 were obviously decreased. ß-Cryptoxanthin treatment induced G0/G1 arrest, and reduced the expression of Cyclin E, Cyclin D1, cyclin-dependent kinases (CDK) of CDK4 and CDK6, and increased the expression of p53 and p21 in the two GC cells. Additionally, ß-cryptoxanthin induced apoptosis and increased the expression of cleaved caspase-3, -8, -9 as well as cytochrome C (cyt C). ß-Cryptoxanthin induced AMP-activated protein kinase (AMPK) signal inactivation by the down-regulation of protein kinase A (PKA), p-AMPK, eukaryotic elongation factor 2 kinase (eEF2k). Furthermore, ß-cryptoxanthin inhibited tumor growth through suppressing the tumor volume and weight, inducing apoptotic cells. Besides, ß-cryptoxanthin induced significant reductions of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). In conclusion, our data provide the novel evidence to understand the mechanism of anti-pcancer of ß-cryptoxanthin and indicate that ß-cryptoxanthin can serve as a promising chemopreventive agent against gastric cancer.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , beta-Criptoxantina/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Oncol Rep ; 42(3): 1101-1109, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322218

RESUMO

The antipsychotic drug pimozide has been found to exhibit anticancer effects. Previously, it was demonstrated that pimozide inhibits hepatocellular carcinoma (HCC) cell growth, but its pharmacodynamic characteristics remain unclear. The aim of the present study was to investigate the reversibility and mechanism of the ability of pimozide to inhibit cell proliferation in liver cancer. Cell viability was determined by Cell Counting Kit­8 and colony formation assay. The cell cycle distribution was analyzed by flow cytometry with Ki­67 and PI staining. ROS production of HCC cells was detected with DCFH­DA and inhibited with NAC treatment. Western blot assay was performed to detect the expression of related signaling molecules in HCC cells. Our results showed that pimozide promoted G0/G1 phase arrest in HCC cell lines without significant cell death. Its anti­proliferative effects on HCC cells were reversible, consistent with involvement of cell quiescence and reactive oxygen species (ROS) production. Pimozide enhanced inhibition of HCC cell proliferation by sorafenib. In conclusion, elucidation of pimozide's reversible proliferation inhibition in liver cancer and additive activity with a well­established anticancer drug warrants further exploration of the potential of pimozide as an adjuvant anticancer therapy.


Assuntos
Antipsicóticos/farmacologia , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Pimozida/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
7.
BMC Complement Altern Med ; 19(1): 188, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351461

RESUMO

BACKGROUND: Apiole was isolated from the leaves of various plants and vegetables and has been demonstrated to inhibit human colon cancer cell (COLO 205 cells) growth through induction of G0/G1 cell cycle arrest and apoptotic cell death. This study further explored the antitumor effects of apiole derivatives AP-02, 04, and 05 in COLO 205 cancer cells. METHODS: Human breast (MDA-MB-231, ZR75), lung (A549, PE089), colon (COLO 205, HT 29), and hepatocellular (Hep G2, Hep 3B) cancer cells were treated with apiole and its derivatives in a dose-dependent manner. Flow cytometry analysis was subsequently performed to determine the mechanism of AP-02-induced G0/G1 cell cycle arrest. The in vivo antitumor effect of AP-02 (1 and 5 mg/kg, administered twice per week) was examined by treating athymic nude mice bearing COLO 205 tumor xenografts. The molecular mechanisms of AP-02-induced antitumor effects were determined using western blot analysis. RESULTS: AP-02 was the most effective compound, especially for inhibition of COLO 205 colon cancer cell growth. The cytotoxicity of AP-02 in normal colon epithelial (FHC) cells was significantly lower than that in other normal cells derived from the breast, lung or liver. Flow cytometry analysis indicated that AP-02-induced G0/G1 cell cycle arrest in COLO 205 cells but not in HT 29 cells (< 5 µM for 24 h, **p < 0.01). Tumor growth volume was also significantly inhibited in AP-02 (> 1 mg/kg)-treated athymic nude mice bearing COLO 205 tumor xenografts compared to control mice (*p < 0.05). Furthermore, G0/G1 phase regulatory proteins (p53 and p21/Cip1) and an invasion suppressor protein (E-cadherin) were significantly upregulated, while cyclin D1 was significantly downregulated, in AP-02-treated tumor tissues compared to the control group (> 1 mg/kg, *p < 0.05). CONCLUSIONS: Our results provide in vitro and in vivo molecular evidence of AP-02-induced anti-proliferative effects on colon cancer, indicating that this compound might have potential clinical applications.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Dioxóis/administração & dosagem , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Petroselinum/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias do Colo/fisiopatologia , Ciclina D1/genética , Ciclina D1/metabolismo , Dioxóis/efeitos adversos , Dioxóis/química , Feminino , Humanos , Camundongos , Camundongos Nus , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Life Sci ; 232: 116610, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254584

RESUMO

AIMS: The aim of this study was the characterization of the in vitro cytotoxic properties of a recently isolated diterpene compound, 7ß-acetoxy-20-hydroxy-19,20-epoxyroyleanone (compound 1), extracted from Salvia corrugata, versus human cell lines. MAIN METHODS: We used as model study immortalized breast epithelial cells MCF10A and two ERBB2+ breast cancer (BCa) cell lines, SKBR-3 and BT474. Compound 1 was isolated by methanolic extraction from regenerated shoots of Salvia corrugata Vahl, and purified by high pressure liquid chromatography (HPLC). Flow cytometry (FCM) was employed for cell cycle, apoptosis and reactive oxygen species (ROS) analysis. Cell morphology was assessed by immunofluorescence and transmission electron microscopy (TEM). KEY FINDINGS: Compound 1 inhibited cell survival of all breast cell lines. In particular, compound 1 promoted cell cycle arrest in the G0/G1 phase and apoptosis along with impairment of the mitochondrial function, which was reflected in a gross alteration of the mitochondrial network structure. Furthermore, we also detected a potent activation of the ERK1/2 kinase, which suggested the induction of reactive oxygen species (ROS). Partial rescue of survival obtained with n-acetylcysteine (NAC) when coadminstered with compound 1 further supported a contribution of ROS mediated mechanisms to the growth-arrest and proapoptotic activity of compound 1 in both BCa cell lines. ROS production was indeed confirmed in SKBR-3. SIGNIFICANCE: Our findings show that compound 1 has a cytotoxic activity against both human normal and cancer cell lines derived from breast epithelia, which is mediated by ROS generation and mitochondrial damage.


Assuntos
Mama/efeitos dos fármacos , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Células Epiteliais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Mama/citologia , Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/isolamento & purificação , Células Epiteliais/metabolismo , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos
9.
Eur J Pharmacol ; 855: 252-261, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085238

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous malignancy of hematopoietic stem cells with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Thus, new therapeutic agents are urgently needed in order to prolong the disease-free survival of AML patients in clinic. Here, we report that BBI608 is highly active against diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, as well as effective in vivo in AML xenograft models. Meanwhile, the anti-AML property of BBI608 is closely associated with the inhibition of Stat3 pathway and induction of DNA damage. Of note, BBI608 combined with Bcl-2 inhibitor (i.e., ABT-199) exerts a significantly enhanced anti-leukemia effect in BBI608-resistant cell line Kasumi-1. Together, the present findings suggest that BBI608 might represent a potential candidate agent for AML treatment.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Dano ao DNA , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Naftoquinonas/farmacologia , Fator de Transcrição STAT3/metabolismo , Adolescente , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzofuranos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Naftoquinonas/uso terapêutico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
10.
Eur J Pharmacol ; 853: 184-192, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928629

RESUMO

Celastrol exhibits anticancer activity and has a number of potential molecular targets. Among them, the proteasome has attracted particular attention. Although celastrol inhibits multiple myeloma (MM) cell proliferation, the induction of proteasome-inhibitory activity by celastrol in MM cells at the cellular level and in tumors of mice bearing xenografts has not been confirmed. In the present study, we found that celastrol inhibited the caspase-like (ß1), trypsin-like (ß2) and chymotrypsin-like (ß5) proteasome activities of purified human 20S proteasomes, with half-maximal inhibitory concentration (IC50) values of 7.1, 6.3, and 9.3 µmol/L, respectively. Celastrol also inhibited human MM cellular ß1, ß2, and ß5 proteasome activities, with IC50 values of 2.3, 2.1, and 0.9 µmol/L, respectively. After MM cells were treated with celastrol, a population of apoptotic cells and a population of cells in G0/G1 were observed. Celastrol also inhibited proteasome activity and induced apoptosis in tumor tissue. Treatment of MM.1S and RPMI 8226 tumor-bearing severe combined immunodeficiency (SCID) mice with celastrol reduced the tumor volume. In conclusion, our results reveal the effects of celastrol on proteasome activity in MM cells and shed light on the underlying mechanisms of its anticancer activity, providing a basis for developing celastrol as a potential therapeutic agent for MM.


Assuntos
Apoptose/efeitos dos fármacos , Mieloma Múltiplo/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nutrients ; 11(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987009

RESUMO

Certain antioxidative flavonoids are known to activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates cellular antioxidants and detoxifying response and is reportedly highly activated in many types of cancers. Few studies on the potential undesired effects of flavonoid intake during chemotherapy have been conducted, yet Nrf2 activators could favor cancer cell survival by attenuating chemotherapeutic efficiency. This study aimed to examine if luteolin, an Nrf2 activator, hinders chemotherapeutic activity of oxaliplatin, a potent anticancer agent for colorectal cancer, in HCT116 cells. Luteolin treatment strongly increased the transcriptional activity of the antioxidant response element in HCT116 cells and induced the protein expression of heme oxygenase-1, which were indicative of its Nrf2-inducing potential. Intriguingly, 25 µM luteolin reduced cell viability through apoptotic induction, which was intensified in p53-expressing cells while 1 µM oxaliplatin caused cell cycle arrest at G0/G1-phase via the p53/p21-dependent mechanism. Moreover, luteolin treatment was found to reduce oxaliplatin-treated p53-null cell viability and colony counts further, thereby demonstrating an additional effect of luteolin in the killing of human colorectal tumor HCT116 cells not expressing functional p53 protein. The findings suggest that luteolin can induce p53-mediated apoptosis regardless of oxaliplatin treatment and may eliminate oxaliplatin-resistant p53-null colorectal cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Luteolina/farmacologia , Oxaliplatina/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Elementos de Resposta Antioxidante/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células HCT116 , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Inflammopharmacology ; 27(5): 1021-1036, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30941613

RESUMO

BACKGROUND: Naringenin, a flavonoid compound, has a wide variety of uses in the pharmaceutical industry for its antioxidant and anti-inflammatory potential. OBJECTIVES: The current experiment aimed to investigate the anticancer effect of naringenin in triple-negative human breast cancer cells (MDA-MR-231) and an animal model with 7,12-dimethylbenz[a] anthracene (DMBA)-induced breast cancer in female rats to determine the mechanisms and molecular targets. METHODS: The cytotoxic effects of naringenin against MDA-MB-231 cells were assessed by MTT assay. Apoptosis and cell cycle alterations were analyzed via flow cytometry. Morphological and biochemical changes in DMBA-induced cancer with naringenin treatment were assayed using our protocol. The potential mechanisms of action were verified via qRT-PCR. RESULTS: Naringenin was found to inhibit cell proliferation in a time- and concentration-dependent manner. This effect was associated with cell cycle arrest at the G0/G1 phase, along with apoptosis and deposition at the sub-G1 phase (75%). Treatment with naringenin reduced tumor incidence (45.55, 40, and 27.67%) and tumor burden (78.7, 35.4, and 1.2 g) in a dose-dependent manner. Naringenin treatment altered the biochemical and antioxidant parameters related to inflammation necessary for anticancer activity. The qRT-PCR studies further confirmed the mitochondrial-mediated apoptotic effects of naringenin. CONCLUSION: On the basis of these results, we can conclude that naringenin exerts an anticancer effect in the MDA-MB-231 cell line that arrests cell development at the G0/G1 phase, and in vivo it alters the mitochondrial-mediated intrinsic pathway responsible for apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Flavanonas/farmacologia , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fase G1/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Wistar , Fase de Repouso do Ciclo Celular/efeitos dos fármacos
13.
J Ethnopharmacol ; 236: 466-473, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30853648

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants have been used for ages by indigenous communities around the world to help humankind sustain its health. Graviola (Annona muricata), also called soursop, is a member of the Annonaceae family and is an evergreen plant that is generally distributed in tropical and subtropical areas of the world. Graviola tree has a long history of traditional use due to its therapeutic potential including anti-inflammatory, antimicrobial, antioxidant, insecticide and cytotoxic to tumor cells. AIM OF THE STUDY: This study aimed to investigate the in vitro antiproliferative effects and apoptotic events of the ionic liquid extract of Graviola fruit (IL-GFE) on MCF-7 breast cancer cells and their cytokinetics behaviour to observe their potential as a therapeutic alternative in cancer treatment. MATERIALS AND METHODS: The cell viability assay of the extract was measured using tetrazolium bromide (MTT assay) to observe the effects of Graviola fruit extract. Then the cytokinetics behaviour of MCF-7 cells treated with IL-GFE is observed by plotting the growth curve of the cells. Additionally, the cell cycle distribution and apoptosis mechanism of IL-GFE action on MCF-7 cancer cells were observed by flow cytometry. RESULTS: IL-GFE exhibited anti-proliferative activity on MCF-7 with the IC50 value of 4.75 µg/mL, compared to Taxol with an IC50 value of 0.99 µg/mL. IL- GFE also reduced the number of cell generations from 3.71 to 1.67 generations compared to 2.18 generations when treated with Taxol. Furthermore, the anti-proliferative activities were verified when the growth rate was decreased dynamically from 0.0077 h to 1 to 0.0035 h-1. Observation of the IL-GFE-treated MCF-7 under microscope demonstrated detachment of cells and loss of density. The growth inhibition of the cells by extracts was associated with cell cycle arrest at the G0/G1 phase, and phosphatidylserine externalisation confirms the anti-proliferation through apoptosis. CONCLUSIONS: ionic liquid Graviola fruit extract affect the cytokinetics behaviour of MCF-7 cells by reducing cell viability, induce apoptosis and cell cycle arrest at the G0/G1 phase.


Assuntos
Annona/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Frutas/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Líquidos Iônicos/química , Células MCF-7 , Medicina Tradicional , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Extratos Vegetais/uso terapêutico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos
14.
Lipids ; 54(1): 99-107, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723897

RESUMO

Vitamin A, referred to as retinol, is an essential nutrient that affects the cell growth and differentiation including adipogenesis. Although previous studies using supraphysiological doses (over 1 µM) of all-trans-retinoic acid (atRA) demonstrated antiadipogenic activity, effects of atRA at various levels on differentiation of 3T3-L1 preadipocytes have not been extensively investigated. Our study showed that the amount of cellular triacylglycerol (TAG) and intensities of Oil-Red-O staining were decreased by supplementing atRA (1 and 10 µM) but increased by low concentrations of atRA (0.01 to 100 nM) compared with the control. Also PPARγ and FABP4 were gradually overexpressed by atRA up to 1 nM but decreased at over 1 nM concentrations. Moreover, mitotic clonal expansion (MCE) and consequential growth-arrest were analyzed as important steps in adipogenesis of 3T3-L1 cells. The 1 nM group showed more cell proliferation and thereafter a higher ratio of the G0/G1 phase on Day 2. Protein levels of S/G2-phase factors were dose dependently increased by atRA up to 1 nM on Day 1, but the factors were highly expressed in higher doses on Day 2. G0/G1 markers were higher at the higher doses of atRA on Day 1; whereas, they were highly expressed in mild or medium doses on Day 2. These data indicate that atRA controls adipogenesis with accompanied changes in cell proliferation and follow-up growth-arrest. These results indicate that atRA can function both as a negative and positive regulator of adipogenesis depending on dosages, providing a strategy for achieving proper nutritional balance for treatment of obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Tretinoína/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Camundongos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Triglicerídeos/metabolismo
15.
Int J Biol Macromol ; 129: 1155-1167, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30660566

RESUMO

αvß3 integrin expressed on cancer cell surfaces is associated with important cancer hallmarks including survival and metastasis and is thus a potential anticancer drug target. Tablysin-15 contains the RGD motif and is a high-affinity αvß3 integrin antagonist. The aim of this study was to investigate the antitumor effect and mechanism of action of tablysin-15 against αvß3 integrin high-expressing breast cancer cell lines in vitro and in vivo. Tablysin-15 dose-dependently inhibited the proliferation, migration, and invasion of two breast cancer cell lines via the αvß3 integrin in vitro. Proliferation inhibition was attributable to G0/G1 phase cell cycle arrest rather than apoptosis or necrosis. Furthermore, tablysin-15 downregulated the activity and mRNA expression of MMP-2/-9, VEGF, and COX-2 but upregulated TIMP-1/-2 mRNA in both cell lines. Further, tablysin-15 suppressed the expression of CDK2, CDK6, cyclin D1, and cyclin E, the phosphorylation of FAK, Akt, GSK-3ß, and ERK, and the nuclear translocation of NF-κB while increasing the expression of the CDK inhibitor p21waf1/C1. Lastly, tablysin-15 provided effective antitumor protection in vivo. Thus, tablysin-15 inhibits the metastasis and proliferation of breast cancer cells through binding αvß3 integrin and blocking FAK-associated signaling pathways as well as nuclear translocation of NF-κB.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Desintegrinas/química , Desintegrinas/farmacologia , Oligopeptídeos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Integrina alfaVbeta3/metabolismo , Camundongos , Invasividade Neoplásica , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Lett ; 447: 130-140, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30677445

RESUMO

Human epidermal growth factor receptor 2 (HER2) is amplified in about 20% breast cancers. Treat of HER2 positive breast cancers has been greatly promoted in last few years, but the accompany HER2 blockade has hindered the therapeutic effect. Pyrotinib is a pan-HER kinase inhibitor that suppresses signaling through the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. Palbociclib is a CDK4/6 inhibitor that inhibits cell cycle progression and cancer cell proliferation in ER+ breast cancers. We hypothesized that the combination of pan-HER kinase inhibitors and CDK4/6 inhibitors would show synergistic antitumor activity in vivo in vitro. Our data show that a combination of palbociclib and pyrotinib was highly synergistic in inhibiting cancer proliferation and colony formation. The combined treatment also induced significant decreases in pAKT and pHER3 activation, induced G0-G1 cell cycle arrest, and increased rates of apoptosis. In the xenograft model, the combination treatment demonstrated greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer a preclinical rationale clinical investigation of the effectiveness of a combination treatment of palbociclib with pyrotinib for breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor ErbB-2/genética , Acrilamidas/farmacologia , Aminoquinolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Exp Mol Pathol ; 107: 95-101, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610843

RESUMO

BACKGROUND: Acoustic neuroma is a benign and usually slow growing tumor. Brazilein is a natural compound extracted from hematoxylin. However, there has been no study of the mechanism of brazilein in acoustic neuroma cells. Thus, we aimed to investigate the effects and mechanism of brazilein on human VS cells in this study. METHODS: The vestibular schwannoma (VS) cells were collected from patient tissues and used in this study. Different concentrations of brazilein (0, 10, 20 and 30 µM) were used to treat VS cells. The expression of miR-133a was altered by transfection with miR-133a inhibitor. Further, cell viability, apoptosis, cell cycle, the mRNA and phosphorylation levels of cell cycle, apoptosis-related proteins and main factors in MAPK and JNK pathways were detected using CCK-8 assay, flow cytometry analysis, qRT-PCR and western blot analysis, respectively. RESULTS: The results showed that brazilein decreased cell viability, increased apoptosis and induced G1/G0 cell cycle arrest in VS Cells. Further, miR-133a expression was up-regulated in the brazilein-treated cells. Brazilein promoted apoptosis and induced G1/G0 cell cycle arrest via up-regulation of miR-133a. In addition, brazilein inhibited the activations of MAPK and JNK pathways by up-regulating miR-133a expression. CONCLUSION: In conclusion, our study demonstrated that brazilein could induce apoptosis and G1/G0 phase cell cycle arrest, and deactivate MAPK and JNK signaling pathways via up-regulation of miR-133a in human VS cells. These results provide theoretical evidence for the clinical application of brazilein and a new strategy for the treatment of acoustic neuroma.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/farmacologia , Indenos/farmacologia , MicroRNAs/biossíntese , Neuroma Acústico/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , MicroRNAs/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Regulação para Cima
18.
Prostate ; 79(2): 151-159, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30242861

RESUMO

BACKGROUND: Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer. METHODS: Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks. RESULTS: WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05). CONCLUSIONS: The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.


Assuntos
Benzoxazinas/farmacologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis/farmacologia , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Distribuição Aleatória , Receptor CB2 de Canabinoide/antagonistas & inibidores , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Eur J Med Chem ; 162: 765-780, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30500683

RESUMO

The mixture of GX (guttiferone E and xanthochymol), an inseparable polycyclic polyprenylated acylphloroglucinol (PPAP), showed moderate cytotoxic activities. The chemical transformation of GX yielded three different types of PPAPs (1, 2, and 3/4). A series of analogs were prepared, and the structures of the 40 newly synthesized compounds were elucidated by 1D and 2D NMR and HR-ESI-MS. The derivatives were screened in vitro for antiproliferative activity against five human cancer cell lines: human leukemic cell lines (HEL and K562), cervical cancer cell line (Hela), human breast adenocarcinoma cell line (MCF-7), and human non-small cell lung cancer cell line (A549), using the MTT assay, and most of the derivatives showed good cytotoxic activities. Noticeably, compound 2, a novel tautomer with a hemiketal, exhibited selective cytotoxic activities against HEL (IC50 = 4.79 ±â€¯0.23 µM) and K562 (IC50 = 7.69 ±â€¯0.34 µM) leukemia cells. The mechanism studies indicated that compound 2 induced apoptosis and arrested the cell cycle at the G0/G1 phase in the HEL cell line. Furthermore, compound 2 activated the intrinsic pathway by reducing the expression of anti-apoptotic protein Bcl-2 and cell cycle-specific cyclin D1 and by enhancing the pro-apoptotic protein Bax. Moreover, the caspase-3 and PPRP1 levels were also upregulated. Our present results suggest that compound 2 is a potential candidate for developing novel anti-leukemia agents in the future.


Assuntos
Apoptose , Benzofenonas/química , Pontos de Checagem do Ciclo Celular , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Ciclina D1/efeitos dos fármacos , Ciclina D1/metabolismo , Citotoxinas , Humanos , Leucemia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Policíclicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Proteína X Associada a bcl-2/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
20.
J Biochem Mol Toxicol ; 33(4): e22280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30485594

RESUMO

To date, there are some chemically synthesized curcumin derivatives which were produced and identified to evade the disadvantages of physiochemical stability and solubility of curcumin. Here, one novel curcumin derivative, (2-(3-{(1E)-{(E)-3-(4-hydroxy-3-methoxybenzylidene)-2-oxocyclohexylidene)methyl)-1H-indol-1-yl)acetic acid}, (abbreviated as MOMI-1) was first used to detect the antiproliferation activity with MTT assays in different cancer cells including A549 lung cancer cells, MCF-7, and HEPG2 cell lines, and exhibited its wide inhibition spectrum. Next, we found that MOMI-1 could induce autophagic genesis of A549 cells by acridine orange or monodansylcadaverine (MDC) staining and green fluorescent protein-light chain 3 (GFP-LC3) recombinant plasmid transfection analysis, respectively. Western blot analysis confirmed the LC3-I/II conversion, beclin-1 increase and p62 reduction of A549 cells after exposure of MOMI-1, which suggested the typical autophagy induction. The following cell cycle test showed that MOMI-1 could block A549 cells in G0/G1 phase. Furthermore, wounding healing experiment and transwell assays demonstrated that MOMI-1 also possessed the antimigration ability of A549 cells. Our current results confirmed that MOMI-1 could inhibit the proliferation and induce autophagy of A549 cells, which provide a new potential chemical candidate of antigrowth of A549 lung cancer cells. Future work needs to focus on the mechanism of autophagy pathway of A549 cells.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Curcumina/análogos & derivados , Curcumina/farmacologia , Células 3T3 , Células A549 , Animais , Fase G1/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
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