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1.
Pathol Res Pract ; 241: 154272, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36525850

RESUMO

Quinones are naturally or synthetically occurring secondary metabolites that have various bio-dynamics, highlighting their antitumor potential. This has been explored through their selective cytotoxicity, and studies in medicinal chemistry about the relation between biological activity versus chemical structure may lead to the solution of the toxicity problems associated with quinones. In this context, the antitumor effect of a synthetic naphthoquinone, named Ethyl 2-(1,4-Dioxo-1,4-Dihydronaphthalen-2-Ylamino) Acetate, was tested using mice transplanted with Ehrlich ascitic tumor as an experimental model. The acute toxicity test was performed using 30 mice that received the aminoquinone at doses of 100, 200, 300, and 600 mg/kg. After evaluation of the clinical findings in the spontaneous activity tests, the LD50 calculation for the test substance showed low levels of toxicity at doses lower than 244.11 ± 23.29 mg/kg. Thus, three experimental groups were established, where animals transplanted with tumor cells received NaCl vehicle solution (control, n = 6), and the others were treated with 71.7 mg/kg of Methotrexate (n = 6) or 20 mg/kg of Aminoquinone (n = 6). All administrations were intraperitoneal, in a single dose. Three days after the implantation of the tumor cells the animals were weighed daily and evaluated for tumor biometry and development. The treatments occurred five days after the implantation of the tumor cells and were extended for 7 more days. At the end of the 12-day experimental period, all animals were euthanized for biochemical and histopathological analyses of the tumors and vital organs. The spontaneous activity test showed that the amount of responses associated with the nervous system tends to increase with the increase in dosage, highlighting the excitatory effect on the central nervous system in almost all dosages employed, followed by depressant activities on this system. There was a significant tumor reduction, both in animals treated with methotrexate (71.7 %) and in those treated with aminoquinone (91.6 %) in the control group. There was no significant difference in tumor volume between the animals treated with aminoquinone or methotrexate. The histopathological analysis revealed that in both treatments there were fewer mitoses in the tumor mass compared to the control group. However, there was apparent toxicity to the liver, heart, and left kidney in the treatment with methotrexate compared to aminoquinone. The significant capacity for tumor reduction presented by aminoquinone allows pointing it as a promising alternative for the development of a more efficient drug to control tumor development, being necessary for the development of new studies to deepen the knowledge about its mechanisms of action.


Assuntos
Carcinoma de Ehrlich , Metotrexato , Camundongos , Animais , Metotrexato/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Coração , Fígado/patologia , Acetatos/farmacologia , Acetatos/uso terapêutico
2.
Molecules ; 27(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36500567

RESUMO

Oroxylum indicum is a traditionally used plant in Ayurvedic and folk medicines. The plant is useful for the management of gastrointestinal diseases as well as skin diseases. In the present study, we analyzed the antitumor potential of O. indicum in Dalton's lymphoma ascites tumor cells (DLA) and Ehrlich ascites carcinoma (EAC)-induced solid and ascites tumors. Further, the potential of O. indicum extract (OIM) on skin papilloma induction by dimethyl benz(a) anthracene (DMBA) and croton oil was evaluated. The chemical composition of the extract was analyzed using UPLC-Q-TOF-MS. The predominant compounds present in the extract were demethoxycentaureidin 7-O-rutinoside, isorhamnetin-3-O-rutinoside, baicalein-7-O-glucuronide, 5,6,7-trihydroxyflavone, 3-Hydroxy-3',4',5'-trimethoxyflavone, 5,7-dihydroxy-3-(4-methoxyphenyl) chromen-4-one, and 4'-Hydroxy-5,7-dimethoxyflavanone. Treatment with high-dose OIM enhanced the percentage of survival in ascites tumor-bearing mice by 34.97%. Likewise, high and low doses of OIM reduced the tumor volume in mice by 61.84% and 54.21%, respectively. Further, the skin papilloma formation was brought down by the administration of low- and high-dose groups of OIM (by 67.51% and 75.63%). Overall, the study concludes that the Oroxylum indicum root bark extract is a potentially active antitumor and anticancer agent.


Assuntos
Bignoniaceae , Carcinoma de Ehrlich , Camundongos , Animais , Extratos Vegetais/química , Bignoniaceae/química , Carcinoma de Ehrlich/tratamento farmacológico , Medicina Tradicional , Óleo de Cróton/uso terapêutico
3.
Med Oncol ; 40(1): 6, 2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36308603

RESUMO

MMR vaccine is a common vaccine that contains oncolytic viruses (Measles, Mumps, and Rubella) and could be used as a potential anti-cancer treatment. In this study, we assessed the anti-tumor activity of the MMR vaccine against Ehrlich ascites carcinoma (EAC) solid tumor induced in mice. The in vitro assay showed that vaccine IC50 in EAC was approximately 200 CCID50. The vaccine was intratumorally administrated twice weekly in EAC-bearing mice. The antitumor response of the vaccine was measured by tumor growth, survival rate, histopathologic examination, flow cytometry analysis, and body biochemical parameters. The MMR vaccine demonstrated a substantial reduction of tumor growth and prolongation of life span as well. The proliferation marker was significantly lower in the vaccine-treated group. Moreover, the apoptosis key parameter Casp-3 was also higher in the vaccine-treated group. The vaccine somewhat restored the deterioration of the biochemical parameters (LDH, GOT, GPT, MDA, NO, and PON-1) in the tumor-bearing mice. Finally, this study indicated the potential antitumor effect of MMR vaccine via anti­proliferative, apoptotic activities, and modulating the antioxidant parameters. This study opens a new field of inquiry for future research on the vaccine's anti-cancer properties.


Assuntos
Carcinoma de Ehrlich , Vacina contra Sarampo-Caxumba-Rubéola , Animais , Camundongos , Vacinas Atenuadas , Ascite , Modelos Animais de Doenças , Carcinoma de Ehrlich/terapia , Carcinoma de Ehrlich/patologia
4.
J Med Food ; 25(11): 1029-1037, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35944260

RESUMO

Selenium has an anti-inflammatory, antioxidant, and possibly antitumoral action. Thus, we hypothesized that this element could be an ally in cancer treatment. We evaluated the effect of chelated selenium treatment of BALB/c mice with Erhlich Tumor on tumor size, histology, and biochemical parameters of the liver. A total of 96 male mice were treated for 7, 15, and 30 days with different doses of chelated selenium. During the 7 days of treatment, livers presented mild hydropic degeneration; after 15 days, the livers presented mild hydropic degeneration, inflammatory infiltrate, and steatosis, which was intensified in the animals treated for 30 days. Biochemical analysis showed an increase of the alanine transaminase enzyme in those animals, indicating hepatotoxicity. At the beginning of treatment, selenium was able to inhibit tumor growth. After 30 days of treatment, however, hepatotoxicity could be seen.


Assuntos
Carcinoma de Ehrlich , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias , Selênio , Masculino , Camundongos , Animais , Selênio/farmacologia , Camundongos Endogâmicos BALB C , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Fígado
5.
Naunyn Schmiedebergs Arch Pharmacol ; 395(10): 1225-1238, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35881165

RESUMO

Despite the advances made in cancer therapeutics, their adverse effects remain a major concern, putting safer therapeutic options in high demand. Since chalcones, a group of flavonoids and isoflavonoids, act as promising anticancer agents, we aimed to evaluate the in vivo anticancer activity of a synthetic isoquinoline chalcone (CHE) in a mice model with Ehrlich solid carcinoma. Our in vivo pilot experiments revealed that the maximum tolerated body weight-adjusted CHE dose was 428 mg/kg. Female BALB/c mice were inoculated with Ehrlich ascites carcinoma cells and randomly assigned to three different CHE doses administered intraperitoneally (IP; 107, 214, and 321 mg/kg) twice a week for two consecutive weeks. A group injected with doxorubicin (DOX; 4 mg/kg IP) was used as a positive control. We found that in CHE-treated groups: (1) tumor weight was significantly decreased; (2) the total antioxidant concentration was substantially depleted in tumor tissues, resulting in elevated oxidative stress and DNA damage evidenced through DNA fragmentation and comet assays; (3) pro-apoptotic genes p53 and Bax, assessed via qPCR, were significantly upregulated. Interestingly, CHE treatment reduced immunohistochemical staining of the proliferative marker ki67, whereas BAX was increased. Notably, histopathological examination indicated that unlike DOX, CHE treatment had minimal toxicity on the liver and kidney. In conclusion, CHE exerts antitumor activity via induction of oxidative stress and DNA damage that lead to apoptosis, making CHE a promising candidate for solid tumor therapy.


Assuntos
Carcinoma de Ehrlich , Chalcona , Chalconas , Animais , Apoptose , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Chalcona/farmacologia , Chalcona/uso terapêutico , Chalconas/farmacologia , Dano ao DNA , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Isoquinolinas/farmacologia , Camundongos , Estresse Oxidativo , Proteína X Associada a bcl-2/genética
6.
Appl Biochem Biotechnol ; 194(11): 5386-5402, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35779177

RESUMO

Seeking for new effectual anticancer drugs is of great importance. In this study, a newly synthesized and well-characterized chromene derivative (ethyl 2-amino-4-phenyl-4H-benzo(h)chromene-3-carboxylate) "C" was prepared. Molecular docking studies were done. The new compound "C" in compare to the natural parent Quercetin "Q," as a well-known natural chromene derivative with antioxidant and antitumor activities, were tested for their antitumor activity against Ehrlich ascites carcinoma (EAC)-bearing mice. Both reduced ascites volume, decreased viable EAC cells, and prolonged EAC-bearing mice life span. They normalized troponin, creatine kinase-MB, lactate dehydrogenase, and urea levels, reversed liver enzyme activities towards normal, and increased antioxidant levels while reduced tumor necrosis factor-alpha (TNF-α) levels. Compared to each other, the new synthetic derivative "C" showed stronger antineoplastic effects than the natural parent "Q" may via the anti-inflammatory activities. Therefore, the newly synthesized chromene derivative is more promising as a future antitumor candidate than the natural parent molecule "Quercetin." Finally, our results encourage researchers to pay more attention to developing more novel natural-based derivatives that would be more beneficial as future therapeutics than their natural parents.


Assuntos
Antineoplásicos , Carcinoma de Ehrlich , Camundongos , Animais , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Fator de Necrose Tumoral alfa , Ascite , Quercetina/uso terapêutico , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzopiranos/uso terapêutico , Troponina/uso terapêutico , Lactato Desidrogenases , Creatina Quinase/uso terapêutico , Ureia
7.
Sci Rep ; 12(1): 11839, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35821255

RESUMO

Cinnamon is a well-known natural spice and flavoring substance used worldwide. The objective of the present work is to explore the possible antitumor and immunomodulatory potencies of cinnamon essential oil (Cinn) on Ehrlich ascites carcinoma (EAC). A total of fifty female Swiss albino mice were sub-grouped into five groups (n = 10), namely, normal (a non-tumorized and non-treated) group; EAC-tumorized and non-treated group; Cinn (non-tumorized mice received Cinn, 50 mg/kg per body weight daily) group; a group of EAC-tumorized mice treated with Cinn and the final positive control group of EAC-tumorized mice received cisplatin. Eight compounds were identified from Cinn using UPLC-MS-Qtof and NMR analysis. Compared to EAC untreated group, Cinn successfully (P < 0.05) inhibited tumor growth by reducing tumor cell count (45%), viability (53%) and, proliferation accompanied by the inhibition of tumor growth rate. Moreover, a significant (P < 0.05) arrest in the cell cycle at G0/G1 phase was noticed following Cinn treatments (~ 24.5%) compared to EAC group. Moreover, Cinn markedly evoked an antitumor immune response by elevating the percentage of splenic T helper (CD3+CD4+) and T cytotoxic (CD3+CD8+) cells. It is noteworthy that Cinn treatments significantly restored different hematological alterations as well as liver and kidney functions in EAC-tumorized mice. In conclusion, results suggest that Cinn has a good antitumor and immunostimulatory potencies against Ehrlich ascites carcinoma in vivo. The mechanism underlying its antitumor activity may be attributed to its immunostimulatory effects which increase its potential as a promising anticancer candidate.


Assuntos
Antineoplásicos Fitogênicos , Carcinoma de Ehrlich , Óleos Voláteis , Animais , Antineoplásicos Fitogênicos/farmacologia , Ascite , Carcinoma de Ehrlich/patologia , Cromatografia Líquida , Cinnamomum zeylanicum , Feminino , Imunidade , Camundongos , Camundongos Endogâmicos , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Espectrometria de Massas em Tandem
8.
Sci Rep ; 12(1): 12150, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840634

RESUMO

Due to having a long history of traditional uses as a functional food, Zingiber zerumbet was selected here to explore the inherent antioxidant and antineoplastic activities of methanolic extract of its rhizome (MEZZR) against Ehrlich ascites carcinoma (EAC) cells. The rich polyphenol containing MEZZR showed a marked DPPH, ABTS, nitric oxide radicals and lipid peroxidation inhibition activity with an IC50 of 3.43 ± 1.25, 11.38 ± 1.39, 23.12 ± 3.39 and 16.47 ± 1.47 µg/ml, respectively, when compared to the standard catechin. In vivo, MEZZR significantly inhibited EAC cell growth, decreased body weight gain, increased life span and restored the altered hematological characteristics of EAC-bearing mice. Moreover, MEZZR induced nuclear condensation and fragmentation, which are notable features of apoptosis as observed by fluorescence microscopy after staining EAC cells of MEZZR-treated mice with Hoechst 33342. Additionally, in vitro, the cell growth inhibition caused by the MEZZR in MTT assay, was remarkably decreased in the presence of caspase-3, -8 and -9 inhibitors. This study thus suggests that MEZZR may possess promising antiproliferative efficacy against EAC cells by inducing cell apoptosis.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Carcinoma de Ehrlich , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ascite , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Rizoma
9.
Appl Radiat Isot ; 187: 110305, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35688071

RESUMO

BACKGROUND: This work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. METHODS: Fifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. RESULTS: Remarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. CONCLUSIONS: The study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.


Assuntos
Carcinoma de Ehrlich , Metformina , Neoplasias , Animais , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/radioterapia , Peroxidação de Lipídeos/efeitos da radiação , Metformina/uso terapêutico , Camundongos
10.
Integr Cancer Ther ; 21: 15347354221096668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35543434

RESUMO

The rising interest in innovative methods of cancer immunotherapy has prompted research into the immunomodulatory mechanisms of natural and synthetic substances. The goal of this study was to assess chrysin immune-stimulating and pro-apoptotic effects on tumor growth and cell susceptibility to ionizing radiation in order to improve cancer therapy. Chrysin (20 mg/kg/day) was intraperitoneally injected to mice bearing 1 cm3 solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole body exposed to 1 Gy of gamma radiation (2 fractionated dose 0.5 Gy each). Treatment with chrysin dramatically reduces tumor proliferation in EAC mice; furthermore, IFN-γ activity is significantly reduced when compared to EAC mice. When compared to EAC mice, the expression of TNF-α, free radicals, and nitric oxide (NO) levels were considerably reduced, along with improvements in apoptotic regulators (caspase-3 activity). Moreover, the histopathological investigation confirms the improvement exerted by chrysin even in the EAC mice group or the EAC + R group. What is more, exposure to gamma radiation sustained the modulatory effect of chrysin on tumor when compared with EAC + Ch mice. Hence, chrysin might represent a potential therapeutic strategy for increasing the radiation response of solid tumor.


Assuntos
Carcinoma de Ehrlich , Animais , Apoptose , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Flavonoides/farmacologia , Raios gama , Humanos , Camundongos
11.
Sci Rep ; 12(1): 6494, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35444229

RESUMO

The burden of cancer diseases is increasing every year, therefore, the demands to figure out novel drugs that can retain antitumor properties have been raised. This study aimed to investigate the anti-tumor properties of amygdalin (Amy) against Ehrlich ascites carcinoma (EAC) bearing mice and its protective properties against liver damage. Amy and the standard anticancer drug Sorafenib (Sor) were given alone or in combination to Swiss albino female mice that had been injected with EAC cells. Biochemical parameters of liver function (AST, ALT, GGT, total protein, albumin), tumor volume, oxidative stress [malondialdehyde, (MDA)] and antioxidative [superoxide dismutase (SOD), and reduced glutathione (GSH)] markers were measured. The hepatic expression of the antioxidant-related gene [nuclear factor erythroid-2-related factor 2 (Nrf2)], the migration-related gene [matrix metalloprotease 9 (MMP9)], and the angiogenesis-related gene [vascular endothelial growth factor (VEGF)] were evaluated by qPCR. The results revealed that EAC-bearing mice treated with Amy and/or Sor showed a decrease in the tumor burden and hepatic damage as evidenced by (1) decreased tumor volume, number of viable tumor cells; (2) increased number of dead tumor cells; (3) restored the liver function parameters; (4) reduced hepatic MDA levels; (5) enhanced hepatic GSH and SOD levels; (6) upregulated expression of Nrf2; (7) downregulated expression of MMP9 and VEGF, and (8) improved hepatic structure. Among all treatments, mice co-treated with Amy (orally) and Sor (intraperitoneally) showed the best effect. With these results, we concluded that the Amy improved the antitumor effect of Sor and had a protective role on liver damage induced by EAC in mice.


Assuntos
Amigdalina , Carcinoma de Ehrlich , Neoplasias , Amigdalina/farmacologia , Animais , Antioxidantes/farmacologia , Ascite , Carcinoma de Ehrlich/patologia , Fígado/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/uso terapêutico , Camundongos , Fator 2 Relacionado a NF-E2 , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Superóxido Dismutase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
12.
Biomed Pharmacother ; 149: 112835, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35325850

RESUMO

Breast cancer remains a leading cause of female mortality worldwide. Therefore, novel complementary treatments have been sought. Recently, there has been a growing interest in investigating the possible complementary effects of polyphenolic compounds against various malignancies. In the present study, using MCF-7 and MDA-MB-231 human breast adenocarcinoma cells, the anticancer efficacy of a polyphenolic mixture (PFM) was investigated. PFM is composed of curcumin, resveratrol, epigallocatechin gallate, and quercetin. PFM treatment led to a dose-dependent inhibition of cell proliferation, with IC50 values of 25.9 ± 3 µg/ml and 29.4 ± 0.9 µg/ml for MCF-7 and MDA-MB-231 cells, respectively. In addition, PFM induced apoptosis in MDA-MB-231 cells and cell cycle arrest at the S phase in MCF-7 cells. Using RT-qPCR, PFM treatment was observed to result in significant downregulation of the oncogenic miR-155 (P < 0.05), as well as significant downregulation of the rate-limiting glycolytic enzyme, hexokinase 2 (HK2) (P < 0.05), while upregulating the expression of the zinc finger E-box binding homeobox 2 gene (P < 0.01). PFM was also found to exert an anti-migration effect in breast cancer cells using the wound healing assay, as well as significantly (P < 0.05) increasing the median survival of Ehrlich ascites carcinoma (EAC) tumor-bearing mice. These results suggest that PFM possesses potential antitumor effects against breast cancer. A possible mechanism of action could be due to PFM's effect in modulating the expression of the glycolytic enzyme HK2 through suppression of miR-155 in MCF-7 cells. Combining polyphenolic compounds that interact with one another could result in synergistic effects that potentially target various tumour hallmarks.


Assuntos
Neoplasias da Mama , Carcinoma de Ehrlich , MicroRNAs , Animais , Antioxidantes/farmacologia , Apoptose , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Células MCF-7 , Camundongos , MicroRNAs/genética , MicroRNAs/farmacologia
13.
Invest New Drugs ; 40(4): 681-689, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35352212

RESUMO

Although many cancer drugs are clinically approved, they still suffer from no adequate efficiency or drug resistance, or bad side effects. Therefore, developing safer alternatives of competitive efficiency is needed. This study aimed to investigate, for the first time, the antitumor and apoptotic activities of palladium(II) 2-hydroxyimino-3-(2-hydrazonopyridyl)-butane complex against Ehrlich carcinoma. In vitro, EAC cells were incubated with the complex, and the cells' viability, caspase 8 activity, and cell cycle changes were evaluated. In vivo, eighty adult female Swiss albino mice were distributed randomly in the following groups (n = 10): Normal, EAC, EAC + Cisplatin, and four groups EAC + Complex as well as Normal + Complex. Bodyweight changes were noted. On day 22 mice were sacrificed. Tumors' volume and weight were recorded. Blood picture was routinely investigated. The median survival time (MST) and percent increase in life span (%ILS) were monitored. In vitro, the complex reduced the %viable EAC cells, increased caspase 8 activity, arrested cell cycle at G0/G1, and reduced G2(M) population indicating antiproliferative and antitumor activities via inducing apoptosis. Treatment with the complex in a dose-dependent mode significantly decreased tumor volume and weight, extended the MST and the %ILS, increased mice body weight gain, and improved the blood indexes. Treatment of EAC-bearing mice with the complex highest dose showed more desirable outcomes than treatment with cisplatin. The Normal + Complex group showed no pathological changes indicating safety. In conclusion, our outcomes recommend the Pd(II) complex as a new optimistic candidate for tumor therapy after further studies for validation.


Assuntos
Carcinoma de Ehrlich , Neoplasias , Animais , Apoptose , Carcinoma de Ehrlich/patologia , Caspase 8/metabolismo , Ciclo Celular , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Camundongos , Paládio/farmacologia , Bases de Schiff/farmacologia , Bases de Schiff/uso terapêutico , Carga Tumoral
14.
Life Sci ; 299: 120497, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35339508

RESUMO

AIMS: This study aims to investigate the potential synergistic effect of the combined treatment of galloylquinic acid compounds from Copaifera lucens with doxorubicin via the modulation of the Notch pathway in solid Ehrlich carcinoma-bearing mice model. MAIN METHODS: The solid tumor model was induced by subcutaneous inoculation of Ehrlich carcinoma cells in the right hind limb of mice, after serial syngeneic cell passages in the peritoneal cavity. Sixty mice were allocated into five groups including treated groups with galloylquinic acid compounds, doxorubicin, and their combination. Normal and tumor control groups were also assigned. Tissue homogenates were collected to measure the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6 and VEGF, as well as SOD, MDA, and GSH. Histopathological and immunohistochemical examinations of tumor or control tissues were also performed for the levels of NF-κB p65, cyclin D1 and caspase 3 activity. KEY FINDINGS: Our results showed that the combined treatment of galloylquinic acid compounds with doxorubicin significantly decreased the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6, VEGF, NF-κB p65, and cyclin D1 in tumor tissues. Moreover, the compounds induced cancer cell death as evidence by increasing the caspase 3 activity, and they possessed potent inhibitory effects on oxidative stress. SIGNIFICANCE: Galloylquinic acid compounds exhibited promising antineoplastic effects and promoted the chemosensitivity of doxorubicin, mainly by modulating the Notch signaling pathway and its downstream effectors. These compounds may be considered in solid tumors treatment for improving the efficacy and reducing the side effects of chemotherapeutic agents.


Assuntos
Antineoplásicos , Carcinoma de Ehrlich , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/patologia , Caspase 3/metabolismo , Ciclina D1/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Interleucina-6/metabolismo , Proteína Jagged-1 , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Biotech Histochem ; 97(8): 555-566, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35240890

RESUMO

Combined use of a chemotherapeutic agent and an autophagy inhibitor is a novel cancer treatment strategy. We investigated the effects of chloroquine (CQ) on lung pathology caused by both solid Ehrlich ascites carcinoma (EAC) and doxorubicin (DXR). A control group and eight experimental groups of adult female mice were inoculated subcutaneously with 2.5 × 106 EAC cells. DXR (1.5 mg/kg and 3 mg/kg) and CQ (25 mg/kg and 50 mg/kg) alone or in combination were injected intraperitoneally on days 2, 7 and 12 following inoculation with EAC cells. Lung tissue samples were examined using immunohistochemistry (IHC) for endothelial (eNOS), inducible nitric oxide synthase (iNOS) and neutrophil gelatinase-associated lipocalin (NGAL). Serum catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using ELISA. We found decreased levels of iNOS and eNOS in the groups that received 1.5 mg/kg DXR alone and in combination with 25 mg/kg and 50 mg/kg CQ. Combined administration of DXR and CQ partially prevented disruption of alveolar structure. Levels of antioxidant enzymes and MDA were lower in all treated groups; the greatest reduction was observed in mice that received the combination of 25 mg/kg CQ + 1.5 mg/kg DXR. Levels of NGAL were elevated in all treated groups. We found that CQ ameliorated both EAC and DOX induced lung pathology in female mice with solid EAC by reducing oxidative stress.


Assuntos
Antioxidantes , Carcinoma de Ehrlich , Animais , Feminino , Camundongos , Antioxidantes/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Catalase/metabolismo , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Doxorrubicina/farmacologia , Glutationa Peroxidase , Lipocalina-2/uso terapêutico , Pulmão/patologia , Malondialdeído , Óxido Nítrico Sintase Tipo II , Superóxido Dismutase/metabolismo
16.
Molecules ; 27(3)2022 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-35164350

RESUMO

Numerous attempts to overcome the poor water solubility of cam ptothecin (CPT) by various nano drug delivery systems are described in various sources in the literature. However, the results of these approaches may be hampered by the incomplete separation of free CPT from the formulations, and this issue has not been investigated in detail. This study aimed to promote the solubility and continuous delivery of CPT by developing long-lasting liposomes using various weights (M.W. 2000 and 5000 Daltons) of the hydrophilic polymer polyethylene glycol (PEG). Conventional and PEGylated liposomes containing CPT were formulated via the lipid film hydration method (solvent evaporation) using a rotary flash evaporator after optimising various formulation parameters. The following physicochemical characteristics were investigated: surface morphology, particle size, encapsulation efficiency, in vitro release, and formulation stability. Different molecular weights of PEG were used to improve the encapsulation efficiency and particle size. The stealth liposomes prepared with PEG5000 were discrete in shape and with a higher encapsulation efficiency (83 ± 0.4%) and a prolonged rate of drug release (32.2% in 9 h) compared with conventional liposomes (64.8 ± 0.8% and 52.4%, respectively) and stealth liposomes containing PEG2000 (79.00 ± 0.4% and 45.3%, respectively). Furthermore, the stealth liposomes prepared with PEG5000 were highly stable at refrigeration temperature. Significant changes were observed using various pharmacokinetic parameters (mean residence time (MRT), half-life, elimination rate, volume of distribution, clearance, and area under the curve) of stealth liposomes containing PEG2000 and PEG5000 compared with conventional liposomes. The stealth liposomes prepared with PEG5000 showed promising results with a slow rate of release over a long period compared with conventional liposomes and liposomes prepared with PEG2000, with altered tissue distribution and pharmacokinetic parameters.


Assuntos
Camptotecina/farmacologia , Camptotecina/farmacocinética , Carcinoma de Ehrlich/tratamento farmacológico , Lipossomos/química , Polietilenoglicóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Liberação Controlada de Fármacos , Técnicas In Vitro , Masculino , Polietilenoglicóis/química , Solubilidade , Distribuição Tecidual
17.
Plant Foods Hum Nutr ; 77(1): 68-76, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34977995

RESUMO

Cancer and cancer-related diseases are a global health concern in the present scenario. Functional food and nutraceuticals are considered as a boon towards cancer management. Amorphophallus commutatus var. wayanadensis (ACW) is an herbaceous plant used by the local communities of Wayanad, India, for food and primary healthcare. Various radical scavenging and reducing power assays were undertaken to evaluate the antioxidant activity of methanolic extract of ACW (MEAC). In vitro anticancer activity was evaluated against HT-29 cell line by MTT assay, morphological analysis, DNA fragmentation assay and cell cycle analysis. Caspase and COX-2 enzyme assays were conducted to examine the underlying mechanism. Studies on Ehrlich Ascites Carcinoma (EAC) transplanted mice models was carried out to evaluate the in-vivo antioxidant and anticancer potential of MEAC. The major bioactive nutraceutical compound present in MEAC was isolated by bioactivity-guided fractionation. MEAC showed significant in vitro antioxidant activity. Further, MEAC promoted cytotoxicity against HT-29 cells by activating caspase-3 dependent apoptotic pathway with a cell cycle arrest at the G1/S phase and subsequent down regulation of COX-2 pathway. The potential antitumor activity of MEAC was further confirmed in EAC tumor bearing mice models in which treatment with MEAC increased the levels of antioxidant enzymes, improved the hematological profile towards normal and also augmented the life span of tumor bearing mice. ß-sitosterol isolated from ACW induces anticancer activity via caspase-dependent pathway. Our study confirmed the antioxidant and anticancer activities of ACW, which proposes the medicinal importance of this plant as a preventive and supportive therapy for arising tumors.


Assuntos
Amorphophallus , Antineoplásicos Fitogênicos , Carcinoma de Ehrlich , Amorphophallus/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/uso terapêutico , Camundongos , Extratos Vegetais/química
18.
Fundam Clin Pharmacol ; 36(3): 536-552, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34984731

RESUMO

Phosphonium compounds offer an attractive branch of research that chemists and biologists apply for producing many novel drugs for various applications, and its polymeric ingredients are composed of quaternary ammonium and phosphonium salts. The reactions of isothiocyanate with phosphinimine bestow thiaziridine, carbamate, and thiourea derivatives. Moreover, isothiocyanate reacts with tris (dimethylamino) phosphine leading to the formation of sulfidomethyl phosphonium. Lawesson's and Japanese reagents have potential to react with isothiocyanates to generate dithiaphosphetane sulfides. Treatment of isocyanate with Lawesson' s or Japanese reagents under reflux conditions affords thiaphosphetidinone sulfide, but when applied at room temperature, the dithiaphosphetane sulfide was isolated. Ehrlich ascites carcinoma (EAC) mice model was used to investigate potential anticancer properties of the novel phosphonium and thiophosphate derivatives. Synthesized compounds (100 mg/kg b.w.) were administered orally to the EAC-bearing mice for about 2 weeks. Compounds' antineoplastic activity was determined by the evaluation of volume, viability, and inhibition percent of EAC cells. In addition, DNA fragmentation percent was assessed. The expression of apoptotic marker genes (Bax, Bcl2, Caspase 3) and encoding proinflammatory cytokines (TNF-α) and pro-apoptotic protein (p53) were inspected by real time-quantitative polymerase chain reaction (RT-qPCR). The overall conclusion was based on the findings that treatment with synthesized compounds leads to decrease in tumor volume, increase in tissue DNA fragmentation, downregulation of Bcl2 gene, and upregulation of Bax, caspase3, and p53 markers, along with decrease in TNF-α level in liver tissues. These findings suggest that the anticancer mechanism of these compounds is based on the programmed cell death (Apoptosis).


Assuntos
Antineoplásicos , Carcinoma de Ehrlich , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Ascite/tratamento farmacológico , Ascite/patologia , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfetos/metabolismo , Sulfetos/farmacologia , Sulfetos/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53 , Proteína X Associada a bcl-2/metabolismo
19.
Carbohydr Polym ; 278: 118941, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34973759

RESUMO

Self-assembled microparticles from chitosan (SAMC) was prepared by depolymerization induced by potassium persulfate. Particle size distribution data showed averaged around 5 µm size and SEM indicated the sequential formation of "RBC" shaped particles. Soluble SAMC consists of 'deacetylated' residues as revealed by 13C NMR. SAMC showed antitumor efficacy in human breast cancer cell lines through mitigation in cell proliferation, colony formation and cell migration. Anti-tumor and anti-angiogenic properties of SAMC was found in vivo Ehrlich ascites tumor (EAT) bearing mice model resulting in tumor growth inhibition (EAT control, 17.4 ml; SAMC treated, 6.8 ml) and improved survival potency (15 days). Moreover, the decrease in ascites VEGF secretion (EAT control, 1354 ng; SAMC treated, 351 ng) accompanied with reduction in neovessel formation. Apoptosis induction by SAMC was confirmed by DNA fragmentation, caspase activities and fluorescence staining methods respectively. SAMC may be a safe candidate for anti-tumor dietary supplement production in food industry.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Quitosana/farmacologia , Neovascularização Patológica/tratamento farmacológico , Animais , Configuração de Carboidratos , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quitosana/síntese química , Quitosana/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia
20.
Mar Drugs ; 20(1)2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35049918

RESUMO

Different classes of phytochemicals were previously isolated from the Red Sea algae Hypnea musciformis as sterols, ketosteroids, fatty acids, and terpenoids. Herein, we report the isolation of three fatty acids-docosanoic acid 4, hexadecenoic acid 5, and alpha hydroxy octadecanoic acid 6-as well as three ceramides-A (1), B (2), and C (3)-with 9-methyl-sphinga-4,8-dienes and phytosphingosine bases. Additionally, different phytochemicals were determined using the liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (LC-ESI-HRMS) technique. Ceramides A (1) and B (2) exhibited promising in vitro cytotoxic activity against the human breast adenocarcinoma (MCF-7) cell line when compared with doxorubicin as a positive control. Further in vivo study and biochemical estimation in a mouse model of Ehrlich ascites carcinoma (EAC) revealed that both ceramides A (1) and B (2) at doses of 1 and 2 mg/kg, respectively, significantly decreased the tumor size in mice inoculated with EAC cells. The higher dose (2 mg/kg) of ceramide B (2) particularly expressed the most pronounced decrease in serum levels of vascular endothelial growth factor -B (VEGF-B) and tumor necrosis factor-α (TNF-α) markers, as well as the expression levels of the growth factor midkine in tumor tissue relative to the EAC control group. The highest expression of apoptotic factors, p53, Bax, and caspase 3 was observed in the same group that received 2 mg/kg of ceramide B (2). Molecular docking simulations suggested that ceramides A (1) and B (2) could bind in the deep grove between the H2 helix and the Ser240-P250 loop of p53, preventing its interaction with MDM2 and leading to its accumulation. In conclusion, this study reports the cytotoxic, apoptotic, and antiangiogenic effects of ceramides isolated from the Red Sea algae Hypnea musciformis in an experimental model of EAC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Ceramidas/farmacologia , Rodófitas , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Organismos Aquáticos , Ascite/patologia , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Ceramidas/química , Ceramidas/uso terapêutico , Modelos Animais de Doenças , Humanos , Oceano Índico , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular
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