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1.
J Exp Zool A Ecol Integr Physiol ; 339(8): 777-787, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37395484

RESUMO

The utility of 5-fluorouracil (5-FU) as a successful chemotherapeutic drug for several cancers is limited by the induction of kidney injury and dysfunction due to redox imbalance, inflammation, and apoptosis. Meanwhile, melatonin (MLT) is a potent antioxidant and anti-inflammatory natural compound with a wide safety range. The current study aimed to investigate MLT's protective effect against 5-FU-induced kidney impairment. Male mice were given multiple doses of 5-FU at 25 and 100 mg/kg, as well as MLT at 20 mg/kg. MLT treatment alleviated the toxic effect of 5-FU by normalizing blood urea and creatinine levels and preserving the histological structure, indicating MLT's nephroprotective ability. This is accompanied by body weight maintenance, an increase in survival percentage, and preserved hematological parameters in comparison to the 5-FU-treated mice. MLT's renoprotective effect was explained by improvements in C-reactive protein, IL-6, and caspase-3 in kidney tissue, indicating MLT's anti-inflammatory and antiapoptotic ability. Furthermore, MLT inhibited 5-FU-induced lipid peroxidation by maintaining the activity of superoxide dismutase and catalase, as well as glutathione levels in kidney tissue from mice treated with both doses of 5-FU. The current findings show that MLT has a novel protective effect against 5-FU-induced renal injury and renal impairment.


Assuntos
Melatonina , Camundongos , Masculino , Animais , Melatonina/farmacologia , Fluoruracila/toxicidade , Fluoruracila/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Rim , Anti-Inflamatórios/farmacologia
2.
Med Oncol ; 40(7): 189, 2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37233859

RESUMO

One of the most common cancers that result in death is lung cancer. There is new hope in the fight against lung cancer thanks to the chemopreventive properties of natural dietary substances like ß-caryophyllene oxide (CPO), and research is currently being done to test this theory. CPO, a sesquiterpene isolated from medicinal plant essential oils, inhibits carcinogenesis and has been effective in treating many cancers. This study examined how CPO affected proliferation of human lung cancer A549 cells. CPO was found to have an inhibitory concentration (IC50) of 124.1 g/ml. The proliferative markers Ki67 and PCNA were significantly inhibited after cells were treated with CPO at a concentration of 50 g/ml compared to controls. CPO-treated cells expressed more P21, P53, and DNA strand breaks than controls. This was accompanied by a significant cell cycle arrest in the S and G2/M phases. In treated A549 cells, this was also associated with a significant induction of apoptosis, as shown by the upregulation of the expression of caspases 3, 7, and 9, as well as Bax, and the downregulation of Bcl-2. Furthermore, the redox status of treated A549 cells revealed a marked rise in GSH and GPx activity levels and a decline in 4-HNE levels, indicating low oxidative stress following CPO treatment of A549 cells. In conclusion, cell cycle arrest and apoptosis, which are unrelated to oxidative stress, were the mechanisms by which CPO reduced cancer lung cell growth. This finding might be a potential therapeutic target for the treatment of lung cancer. Hypothetical scheme of CPO anticancer effects (mechanism of signaling) in A549 cells; in vitro. CPO treatment increases expression of p21, p53 and DNA fragmentation. These events cause arrest of cell cycle which was associated with significant induction in apoptosis via increase expression of caspases (-3,-7,-9), and Bax and downregulation of Bcl-2.


Assuntos
Neoplasias Pulmonares , Proteína Supressora de Tumor p53 , Humanos , Células A549 , Proteína X Associada a bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Divisão Celular , Caspases/metabolismo , Caspases/farmacologia , Caspases/uso terapêutico , Proliferação de Células
3.
Future Med Chem ; 13(19): 1655-1677, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34427101

RESUMO

Hepatocellular carcinoma is a highly aggressive and difficult-to-treat type of cancer. Incorporating urea functionality into the backbone of organoselenium compounds is expected to develop promising chemotherapeutic leads against liver cancer. Methods: Urea-functionalized organoselenium compounds were synthesized in good yields, and their cytotoxicity was evaluated against HepG2 cells. Results: 1,1'-(Diselanediylbis(4,1-phenylene))bis(3-phenylurea) (14) exhibited efficient anti-HepG2 activity in sub-micromolar concentrations, with no toxicity to normal human skin fibroblasts. The molecular mechanisms of the diselenide-based urea 14 were evaluated using colony formation, wound healing, 3D spheroid invasion assays, cell cycle analysis and apoptosis induction. Its redox properties were also assessed by using different bioassays. Conclusion: Our study revealed promising anticancer, antimigratory and anti-invasiveness properties of 1,1'-(diselanediylbis(4,1-phenylene))bis(3-phenylurea) (14) against HepG2.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Ureia/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , Compostos Organosselênicos/química , Ureia/química
4.
Bioorg Chem ; 109: 104713, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33611136

RESUMO

Despite all recent advances in the treatment of hepatocellular carcinoma (HCC), chemotherapy resistance still represents a major challenge in its successful clinical management. Chemo-sensitization offers an attractive strategy to counter drug resistance. Herein we report the identification of novel organoselenium-based pseudopeptides as promising highly effective chemo-sensitizers in treating HCC with cisplatin. A series of functionalized pseudopeptide- (5-9 and 17-19), peptidomimetic- (10-12 and 20-23), and tetrazole-based (13-16 and 24-27) organoselenium compounds were synthesized via isonitrile-based multicomponent reactions from two novel selenium-containing isocyanides. All compounds were evaluated for their cytotoxicity against HepG2 and the non-cytotoxic doses were used to restor the sensitivity of the cells to cisplatin. New organoselenium compounds (7, 9, 15, or 23) led to an effective chemo-sensitization of HepG2 cells towards cisplatin (up-to 27-fold). Cell cycle studies indicate that the most potent peptidomimetic diselenide 23 arrested cells at the S phase and induced apoptosis via ROS modulation.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Compostos Organosselênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Espécies Reativas de Oxigênio
5.
BMC Complement Med Ther ; 20(1): 127, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345289

RESUMO

BACKGROUND: The popularity of fermented foods such as kefir, kuniss, and tofu has been greatly increasing over the past several decades, and the ability of probiotic bacteria to exert anticancer effects has recently become the focus of research. While we have recently demonstrated the ability of the novel kefir product PFT (Probiotics Fermentation Technology) to exert anticancer effects in vitro, here we demonstrate its ability to inhibit Ehrlich ascites carcinoma (EAC) in mice. METHODS: Mice were inoculated intramuscularly with EAC cells to develop solid tumors. PFT was administered orally (2 g/kg/day) to mice 6 days/week, either 2 days before tumor cell inoculation or 9 days after inoculation to mice bearing solid tumors. Tumor growth, blood lymphocyte levels, cell cycle progression, apoptosis, apoptotic regulator expression, TNF-α expression, changes in mitochondrial membrane potential (MMP), PCNA, and CD4+ and CD8+ T cells in tumor cells were quantitatively evaluated by flow cytometry or RT-PCR. Further studies in vitro were carried out where EAC cells along with several other human cancer cell lines were cultured in the presence of PFT (0-5 mg/mL). Percent cell viability and IC50 was estimated by MTT assay. RESULTS: Our data shows that PFT exerts the following: 1) inhibition of tumor incidence and tumor growth; 2) inhibition of cellular proliferation via a marked decrease in the expression of tumor marker PCNA; 3) arrest of the tumor cell cycle in the sub-G0/G1 phase, signifying apoptosis; 4) induction of apoptosis in cancer cells via a mitochondrial-dependent pathway as indicated by the up-regulation of p53 expression, increased Bax/Bcl-2 ratio, decrease in the polarization of MMP, and caspase-3 activation; and 5) immunomodulation with an increase in the number of infiltrating CD4+ and CD8+ T cells and an enhancement of TNF-α expression within the tumor. CONCLUSIONS: PFT reduces tumor incidence and tumor growth in mice with EAC by inducing apoptosis in EAC cells via the mitochondrial-dependent pathway, suppressing cancer cell proliferation, and stimulating the immune system. PFT may be a useful agent for cancer prevention.


Assuntos
Apoptose , Carcinoma de Ehrlich/terapia , Imunomodulação , Kefir , Probióticos/uso terapêutico , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Camundongos
6.
Carcinogenesis ; 38(2): 184-195, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27881463

RESUMO

Many purified compounds from dietary sources have been investigated for their anticancer activities. The main issue with most agents is their effectiveness at high doses which generally could not be delivered to humans through dietary consumption. Here, we observed that cucurbitacin B, a tetracyclic triterpenoid present in pumpkins, gourds and squashes, exhibits antiproliferative effects on human non-small cell lung cancer (NSCLC) cells at nanomolar concentrations. Treatment with cucurbitacin B (0.2-0.6 µM; 24 h) was found to result in decrease in the viability of EGFR-wild type (A549 and H1792) and EGFR-mutant lung cancer cells (H1650 and H1975) and reduction in cell-colonies but had only minimal effect on normal human bronchial epithelial cells. Treatment with cucurbitacin B also caused inhibition of PI3K/mTOR and signal transducer and activator of transcription (STAT)-3 signaling along with simultaneous activation of AMPKα levels in both EGFR-wild type and EGFR-mutant lung cancer cells. Cucurbitacin B caused specific increase in the protein and mRNA expression of sestrin-3 in EGFR-mutant lung cancer cells, but not in EGFR-wild type cells. Treatment with cucurbitacin B to sestrin-3 siRNA treated EGFR-mutant cells further amplified the decrease in cell-viability and caused more sustained G2-phase cell cycle arrest, suggesting that these effects are mediated partly through sestrin-3. We also found that sestrin-3 has a role in the induction of apoptosis by cucurbitacin B in both EGFR-wild type and EGFR-mutant lung cancer cells. These findings suggest novel mechanism by the modulation of sestrin-3 for the action of cucurbitacin B and suggest that it could be developed as an agent for therapy of NSCLC.


Assuntos
Receptores ErbB/genética , Proteínas de Choque Térmico/biossíntese , Neoplasias Pulmonares/tratamento farmacológico , Triterpenos/administração & dosagem , Células A549 , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/efeitos dos fármacos
7.
Carcinogenesis ; 35(2): 415-23, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24072771

RESUMO

In preclinical animal models, several phytochemicals have shown excellent potential to be used as effective agents in preventing and treating many cancers. However, the limited bioavailability of active agents could be one reason for their restricted usefulness for human consumption. To overcome this limitation, we recently introduced the concept of nanochemoprevention by encapsulating useful bioactive food components for their slow and sustained release. Here, we report the synthesis, characterization and efficacy assessment of a nanotechnology-based oral formulation of chitosan nanoparticles encapsulating epigallocatechin-3-gallate (Chit-nanoEGCG) for the treatment of prostate cancer (PCa) in a preclinical setting. Chit-nanoEGCG with a size of <200nm diameter and encapsulating EGCG as determined by dynamic light scattering and transmission electron microscope showed slow release of EGCG in simulated gastric juice acidic pH and faster release in simulated intestinal fluid. The antitumor efficacy of Chit-nanoEGCG was assessed in subcutaneously implanted 22Rν1 tumor xenografts in athymic nude mice. Treatment with Chit-nanoEGCG resulted in significant inhibition of tumor growth and secreted prostate-specific antigen levels compared with EGCG and control groups. In tumor tissues of mice treated with Chit-nanoEGCG, compared with groups treated with EGCG and controls, there was significant (i) induction of poly (ADP-ribose) polymerases cleavage, (ii) increase in the protein expression of Bax with concomitant decrease in Bcl-2, (iii) activation of caspases and (iv) reduction in Ki-67 and proliferating cell nuclear antigen. Through this study, we propose a novel preventive and therapeutic modality for PCa using EGCG that addresses issues related to bioavailability.


Assuntos
Catequina/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Nanopartículas/administração & dosagem , Nanotecnologia , Neoplasias da Próstata/prevenção & controle , Chá/química , Administração Oral , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacologia , Caspases/metabolismo , Catequina/administração & dosagem , Catequina/farmacologia , Ensaio de Imunoadsorção Enzimática , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Nus , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
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