Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.233
Filtrar
1.
Front Immunol ; 13: 954885, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341441

RESUMO

Background: Intestinal mucositis is one of the most common and important side effects of 5-fluorouracil (5-FU). Currently, there are still no specific and effective protocols for its prevention and treatment. The aim of the present study was to evaluate the effect of oral administration of Lacticaseibacillus casei (L. casei) on the progression of 5-FU-induced intestinal mucositis. Methods: L. casei (1x109 CFU/ml) or saline was orally administered to Swiss mice, beginning 15 days before intestinal mucositis induction by single intraperitoneal 5-FU administration (450 mg/kg). Body weight, number of peripheral leukocytes and fecal lactic acid bacteria were monitored. After euthanasia, on day 18, tissue samples from colon and each small intestine segment were collected for histopathology. Jejunal tissues were collected and evaluated for iNOS and TNF-alpha immunoexpression, IL-1-beta, IL-6 and TNF-alpha levels, malonaldehyde (MDA) accumulation, invertase activity and factor nuclear kappa B (NFkB-P65) gene expression, toll like receptor-4 (TLR-4), mucin-2 (MUC-2), occludin and zonula occludens-1 (ZO-1). Results: The positive impact of L. casei on 5-FU-induced leukopenia was observed, but not on 5-FU-induced weight loss in mice. L. casei reduced 5-FU-induced inflammation in the colon and small intestine (p<0.05). Decreased TNF-α, IL-1ß, IL-6 (p<0.05) and MDA (p<0.05) levels, as well as decreased iNOS and TNF-alpha protein expressions (p<0.05) were found in the jejunum from L casei group. In addition, L-casei down-regulated NFKB-P65 (p<0.05) and TLR-4 (p<0.05) gene expressions and up-regulated MUC-2 and mucosal barrier proteins occludin and ZO-1 gene expressions (p<0.05). Furthermore, greater lactic acid bacteria population (p<0.05) was found in the L. casei group when compared to control groups. Conclusion: Oral L. casei administration can protect the intestine of Swiss mice from 5-FU-induced intestinal mucositis, thus contributing to overall health.


Assuntos
Lactobacillus casei , Mucosite , Camundongos , Animais , Fluoruracila/farmacologia , Mucosite/induzido quimicamente , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Ocludina/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Colo/patologia
2.
Molecules ; 27(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36364081

RESUMO

The present study was aimed at examining the anti-tumor effects and molecular mechanisms of 2'-fucosyllactose (2'-FL). At the beginning, the viabilities of four types of colon cancer cells were analyzed after exposure to increasing concentrations of 2'-FL, and HCT116 cells were selected as the sensitive ones, which were applied in the further experiments; then, interestingly, 2'-FL (102.35 µM) was found to induce apoptosis of HCT116 cells, which coincides with significant changes in VEGFA/VEGFR2/p-PI3K/p-Akt/cleaved Caspase3 proteins. Next, in a tumor-bearing nude mouse model, HCT116 was chosen as the sensitive cell line, and 5-fluorouracil (5-Fu) was chosen as the positive medicine. It was noteworthy that both 2'-FL group (2.41 ± 0.57 g) and 2'FL/5-Fu group (1.22 ± 0.35 g) had a significantly lower tumor weight compared with the control (3.87 ± 0.79 g), suggesting 2'-FL could inhibit colon cancer. Since 2'-FL reduced the number of new blood vessels and the malignancy of tumors, we confirmed that 2'-FL effectively inhibited HCT116 tumors, and its mechanism was achieved by regulating the VEGFA/VEGFR2/PI3K/Akt/Caspase3 pathway. Moreover, though HE staining and organ index measurement, 2'-FL was validated to alleviate toxic effects on liver and kidney tissue when combining with 5-Fu. In conclusion, 2'-FL had certain anti-tumor and detoxification effects.


Assuntos
Neoplasias do Colo , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Células HCT116 , Apoptose , Neovascularização Patológica , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células
3.
PLoS One ; 17(11): e0276990, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36327302

RESUMO

Despite multidisciplinary therapy, the prognosis is poor for esophageal squamous cell carcinoma (ESCC). In the locally advanced stage, neoadjuvant chemoradiotherapy (nCRT) followed by surgery could provide survival benefits to some patients. Here, we aimed to identify for tumor therapy response a biomarker based on RNA sequencing. We collected endoscopic biopsies of 32 ESCC patients, who were divided according to nCRT response, into two groups: the complete response group (n = 13) and the non-complete response group (n = 19). RNA-sequencing data showed that 464 genes were differentially expressed. Increased in non-complete response group, 4 genes increased expressions were AGR2 (anterior gradient 2), GADD45B (growth arrest and DNA damage inducible beta), PPP1R15A (protein phosphatase 1 regulatory subunit 15A) and LRG1 (leucine rich alpha-2-glycoprotein 1). The areas under the curve (AUC) of the AGR2 gene was 0.671 according to read counts of RNA-seq and therapy response of nCRT. In vitro study showed that apoptosis cell was significantly increased in the AGR2-knockdown TE-2 cell line treated with cisplatin and 5-Fluorouracil (5-FU), when compared with si-control. Results suggest that in ESCC, the AGR2 gene is a promising and predictive gene marker for the response to anti-tumor therapy.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/terapia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Quimiorradioterapia/métodos , Terapia Neoadjuvante/métodos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Biomarcadores , Esofagectomia/métodos , Mucoproteínas/genética , Proteínas Oncogênicas/genética
4.
Cell Rep ; 41(7): 111625, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384132

RESUMO

Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis. Following a small-molecule inhibitor screen of 1,846 bioactive compounds against a Fn CRC isolate, we find that 15% of inhibitors are antineoplastic agents including fluoropyrimidines. Validation of these findings reveals that 5-fluorouracil (5-FU), a first-line CRC chemotherapeutic, is a potent inhibitor of Fn CRC isolates. We also identify members of the intratumoral microbiota, including Escherichia coli, that are resistant to 5-FU. Further, CRC E. coli isolates can modify 5-FU and relieve 5-FU toxicity toward otherwise-sensitive Fn and human CRC epithelial cells. Lastly, we demonstrate that ex vivo patient CRC tumor microbiota undergo community disruption after 5-FU exposure and have the potential to deplete 5-FU levels, reducing local drug efficacy. Together, these observations argue for further investigation into the role of the CRC intratumoral microbiota in patient response to chemotherapy.


Assuntos
Neoplasias Colorretais , Microbiota , Humanos , Fusobacterium nucleatum , Escherichia coli , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Neoplasias Colorretais/patologia
5.
PLoS Comput Biol ; 18(11): e1010685, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36395103

RESUMO

5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization.


Assuntos
Antineoplásicos , Neoplasias do Colo , Humanos , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Antineoplásicos/farmacologia , Simulação por Computador
6.
Molecules ; 27(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36364474

RESUMO

A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a-r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC50 = 2.04 µM) and 15r (IC50 = 0.85 µM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC50 = 5.31 µM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G0/G1 phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 µM and 1 µM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, ß-catenin, TAB-182, ß-actin, AXIN-2, and NF-κB markers that are involved in the ß-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.


Assuntos
Antineoplásicos , Tanquirases , Humanos , beta Catenina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Antineoplásicos/farmacologia , Apoptose , Fluoruracila/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular
7.
Commun Biol ; 5(1): 1159, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316440

RESUMO

Despite the fact that 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), the response rates in patients is limited to 50%. The mechanisms underlying 5-FU toxicity are debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic heterogeneity, relate to the 5-FU response remains obscure. This largely relies on the limited number of studies performed in pre-clinical models able to recapitulate the key features of CRC. Here, we analyzed the 5-FU response in patient-derived organoids that reproduce the different stages of CRC. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death in the actively proliferating cancer cells deficient in p53. Importantly, p53-deficiency leads to cell death due to impaired cell cycle arrest. Moreover, we find that targeting the Warburg effect in KRASG12D glycolytic tumor organoids enhances 5-FU toxicity by further altering the nucleotide pool and, importantly, without affecting non-transformed WT cells. Thus, p53 emerges as an important factor in determining the 5-FU response, and targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.


Assuntos
Neoplasias Colorretais , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Glucose
8.
Int J Nanomedicine ; 17: 5049-5061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325149

RESUMO

Background: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro. Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs. Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration. Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.


Assuntos
Colite , Neoplasias Colorretais , Camundongos , Animais , Azoximetano/toxicidade , Azoximetano/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Lipossomos/uso terapêutico , Sulfato de Dextrana/toxicidade , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Lipopolissacarídeos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Colite/induzido quimicamente
9.
Bioorg Chem ; 129: 106174, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36191428

RESUMO

A series of novel nitric oxide (NO)-releasing 5,8-quinolinedione/furoxan hybrids (8a-h and 9a-h) were designed and synthesized through coupling different alkanolamine substituted phenylsulfonyl furoxan with 5,8-quinolinedione. Most compounds displayed high cytotoxic activity against drug-sensitive/-resistant cancer cells. In particular, the IC50 of 9a (0.42 µM) was about 9-fold lower than that of ß-lap (3.69 µM) and 12-fold lower than that of SAHA (5.24 µM) in drug-resistant cancer cells. Also, 9a was demonstrated to selectively inhibit the growth of Bel7402/5-FU cancer cells. Mechanistic studies demonstrated that 9a could serve as an NO donor and nicotinamide quinone oxidoreductase 1 (NQO1) inhibitor (IC50 = 0.8 µM), which could induce the highest level of NO and reactive oxygen species (ROS) in Bel-7402/5-FU cancer cells. Furthermore, 9a could promote tumor cell apoptosis and autophagy via regulation of apoptosis-related protein (Bax, Bcl-2, and Caspase 3) and autophagy-associated proteins (LC3 and p62) in Bel-7402/5-FU cells. Taken together, 9a may be considered as a promising candidate for a further comprehensive study involving drug-resistant hepatocellular carcinoma.


Assuntos
Antineoplásicos , Neoplasias Hepáticas , Humanos , Óxido Nítrico/metabolismo , Niacinamida/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Apoptose , Neoplasias Hepáticas/tratamento farmacológico , Fluoruracila/farmacologia , Proliferação de Células , NAD(P)H Desidrogenase (Quinona)
10.
Pathol Res Pract ; 239: 154139, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36191447

RESUMO

BACKGROUND: Endothelin-1 (ET-1) is a peptide overexpressed in gastric cancer (GC) and linked to carcinogenesis and resistance to chemotherapy. Applying microRNAs (miRNAs/miRs) to downregulate ET-1 and reverse resistance to commonly used chemotherapy drugs such as 5-fluorouracil (5-FU) is practical. METHODS: The current study sought to evaluate the miR-648 expression in GC and any plausibility of its replacement, either with or without the combination of chemo agents to downregulate ET-1 expression through interaction with its target gene. To this end, miR-648 and ET-1 expression levels were assessed in GC tissues and adjacent non-tumor tissues driven from 65 patients who had already undergone surgery, fifteen of which had received 5-FU before surgery. The impact of miR-648 and chemo agents on ET-1 expression was measured using qPCR and Western blotting. Further, an MTT assay was conducted to assess its association with cell viability. Ultimately, the association of miR-648 and ET-1 with clinicopathological characteristics was evaluated. RESULTS: The current study revealed that miR-648 was considerably down-regulated, while ET-1 was substantially up-regulated in patients with GC. The 5-FU caused a significant increase in miR-648 and reduced ET-1 expression. It was also determined that overexpression of miR-648 suppressed ET-1 production, notably when combined with 5-FU, leading to survival reduction. These results further showed that miR-648 replacement could sensitize chemoresistant GC cells. Besides, a significant association between ET-1 and miR-648 with clinicopathological features was discovered CONCLUSIONS: miR-648 replacement may serve as a potential oncosuppressive therapeutic approach that warrants further investigation to translate into an effective GC treatment.


Assuntos
MicroRNAs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Fluoruracila/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células
11.
Mol Carcinog ; 61(12): 1177-1190, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36239547

RESUMO

5-Fluorouracil (5-FU) resistance is one of the main causes for treatment failure in esophageal cancer (EC). Here, we intended to elucidate the mechanism of tumor-derived extracellular vesicles (TEVs)-encapsulated long noncoding RNAs (lncRNAs) AC116025.2 in 5-FU resistance in EC. EVs were isolated from the serum samples of EC patients and HEEC, TE-1, and TE-1/5-FU cells, followed by RT-qPCR detection of AC116025.2 expression in EVs. The relationship among AC116025.2, microRNA (miR)-4496, and SEMA5A was evaluated. Next, EC cells were cocultured with EVs, followed by lentivirus transduction and plasmid transfection for studying the role of TEVs-AC116025.2 in EC cells in relation to miR-4496 and SEMA5A. Tumor formation in nude mice was applied for in vivo confirmation. Elevated AC116025.2 expression was seen in the EVs from the serum of 5-FU insensitive patients and from 5-FU-resistant EC cells. Mechanistically, AC116025.2 bound to miR-4496 that inversely targeted SEMA5A in EC cells. EVs-oe-AC116025.2 augmented EC cell viability, colony formation, and 5-FU resistance, but diminished their apoptosis through miR-4496-mediated SEMA5A. Furthermore, EVs-oe-AC116025.2 augmented tumor formation and 5-FU resistance of EC cells in vivo. Conclusively, our data offered evidence of the promoting mechanism of TEVs in the 5-FU resistance of EC by delivering AC116025.2.


Assuntos
Neoplasias Esofágicas , Vesículas Extracelulares , MicroRNAs , RNA Longo não Codificante , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fluoruracila/farmacologia , Camundongos Nus , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral
12.
DNA Cell Biol ; 41(10): 893-902, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36264549

RESUMO

The sperm-associated antigen 5 (SPAG5) is an important protein in mitosis and cell cycle checkpoint regulation, with more attention as a novel oncogene in various cancers. High level of SPAG5 expression has been detected in our clinical gastric cancer (GC) samples and The Cancer Genome Atlas GC data. However, the bio-function and potential mechanism of SPAG5 in GC remain unclear. In this study, we investigated the role of SPAG5 in GC development and the correlation between SPAG5 and 5-fluorouracil (5-FU) treatment. SPAG5 expression was increased in GC samples compared with that in normal tissues (80.8% vs. 22.0%), which was apparently associated with a worse outcome. Biological experiments showed that knockdown of SPAG5 induced apoptosis and suppressed proliferation in cells and animal models. Downregulation of SPAG5 enhanced the sensitivity of 5-FU in GC cells. Gene microarray chip identified 856 upregulated and 787 downregulated genes in SPAG5 silencing cells. Furthermore, 12 significant genes, including CDKN1A, CDKN1B, EIF4E, MAPK1, and HSP90B1, belonged to the PI3K/AKT signaling pathway using ingenuity pathway analysis. Meanwhile, real-time PCR and Western blotting results showed that knockdown of SPAG5 inhibited PI3K/AKT signaling pathway. Collectively, SPAG5 promotes the growth of GC cells by regulating PI3K/AKT signaling pathway, which could be the promising target gene in GC therapy.


Assuntos
Neoplasias Gástricas , Animais , Masculino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Regulação para Cima , Linhagem Celular Tumoral , Sêmen/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico
13.
Int J Mol Sci ; 23(19)2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36232997

RESUMO

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME-administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 µM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.


Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Proliferação de Células , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/farmacologia , Humanos , Isoxazóis/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Purinas/farmacologia , Pirimidinas/química , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Int J Mol Sci ; 23(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36233202

RESUMO

Timosaponin A3 (TA3), extracted from the rhizome of Anemarrhenaasphodeloides Bunge, has been reported to affect various diseases, such as cancer, Alzheimer's disease, and allergies. However, the underlying molecular mechanisms and impacts are largely unknown. In the present study, we hypothesized that TA3 induces apoptosis through the inhibition of c-Myc expression via CNOT2 or MID1IP1 in HCT116. An MTT assay and colony formation assay were used to measure cell viability and proliferation. The protein expression of apoptotic markers and oncogenes was measured using immunoblotting and immunofluorescence assays. The interaction between MID1IP1 and c-Myc was confirmed by performing an immunoprecipitation assay. TA3 markedly inhibited colon cancer cell proliferation. Consistently, TA3 regulated the apoptotic proteins pro-PARP and caspase 3. TA3 inhibited the half-life of c-Myc and suppressed its expression in response to serum stimulation. In addition, TA3 enhanced the apoptotic effects of doxorubicin and 5-FU in colon cancer cells. Altogether, our results reveal a mechanism by which TA3 induces apoptosis through inhibiting c-Myc expression via CNOT2 or MID1IP1 in HCT116, which may help in the development of new therapies for colon cancer based on TA3 in the future.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Células HCT116 , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Repressoras , Saponinas , Esteroides
15.
J Med Chem ; 65(21): 14553-14577, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36269639

RESUMO

Resistance to 5-FU reduces its clinical efficacy for the treatment of colorectal cancer. Sphingosine-1-phosphate receptor 2 (S1PR2) has emerged as a potential target to reverse 5-FU-resistance by inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). In this study, 38 novel S1PR2 antagonists based on aryl urea structure were designed and synthesized, and the structure-activity relationship was investigated based on the S1PR2 binding assay. Representative compound 43 potently interacts with S1PR2 with a KD value of 0.73 nM. It displays potent 5-FU resensitizing activity in multiple 5-FU-resistant tumor cell lines, particularly in SW620/5-FU (EC50 = 1.99 ± 0.03 µM) but shows no cytotoxicity in the normal colon cell line NCM460 up to 1000 µM. Moreover, 43 significantly enhances the antitumor efficacy of 5-FU in the SW620/5-FU animal model. These data suggest that 43 could be a novel lead compound for developing a 5-FU resensitizing agent.


Assuntos
Neoplasias Colorretais , Fluoruracila , Animais , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Receptores de Esfingosina-1-Fosfato , Di-Hidrouracila Desidrogenase (NADP) , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia
16.
AAPS J ; 24(6): 108, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229752

RESUMO

The multi-drug combination regime, FOLFIRINOX, is a standard of care chemotherapeutic therapy for pancreatic cancer patients. However, systematic evaluation of potential pharmacodynamic interactions among multi-drug therapy has not been reported previously. Here, pharmacodynamic interactions of the FOLFIRINOX agents (5-fluorouracil (5-FU), oxaliplatin (Oxa) and SN-38, the active metabolite of irinotecan) were assessed across a panel of primary and established pancreatic cancer cells. Inhibition of cell proliferation was quantified for each drug, alone and in combination, to obtain quantitative, drug-specific interaction parameters and assess the nature of drug interactions. The experimental data were analysed assuming Bliss independent interactions, and nonlinear regression model fitting was conducted in SAS. Estimates of the drug interaction term, psi (ψ), revealed that the Oxa/SN-38 combination appeared synergistic in PANC-1 (ψ = 0.6, 95% CI = 0.4, 0.9) and modestly synergistic, close to additive, in MIAPaCa-2 (ψ = 0.8, 95% CI = 0.6, 1.0) in 2D assays. The triple combination was strongly synergistic in MIAPaCa-2 (ψ = 0.2, 95% CI = 0.1, 0.3) and modestly synergistic/borderline additive in PANC-1 2D (ψ = 0.8, 95% CI = 0.6, 1.0). The triple combination showed antagonistic interactions in the primary PIN-127 and 3D PANC-1 model (ψ > 1). Quantitative pharmacodynamic interactions have not been described for the FOLFIRINOX regimen; this analysis suggests a complex interplay among the three chemotherapeutic agents. Extension of this pharmacodynamic analysis approach to clinical/translational studies of the FOLFIRINOX combination could reveal additional pharmacodynamic interactions and guide further refinement of this regimen to achieve optimal clinical responses.


Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Técnicas de Cultura de Células , Combinação de Medicamentos , Fluoruracila/farmacologia , Humanos , Irinotecano/farmacologia , Leucovorina , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico
17.
Biomed Pharmacother ; 156: 113875, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36272266

RESUMO

5-Fluorouracil (5-FU) is an analog of pyrimidine and has been shown to display antitumor and immunomodulatory effects. However, the impacts of 5-FU in regulating asthma, an inflammatory disease associated with T helper cell 2 (Th2) responses, remain unclear. Here, we determine the modulatory effects of low-dose 5-FU on Th2 cell responses in asthma and delineate the underlying mechanisms using adoptive cell transfer and in vitro culture experiments. Our data show that low-dose 5-FU treatment not only inhibits the induction of asthma in allergen-sensitized mice but also abrogates the major features of asthma in mice with established disease. We find that this protection of 5-FU treatment against asthma is accompanied by a decrease in the number of lung monocyte-derived dendritic cells (moDCs) in the asthmatic murine. Furthermore, we show that adoptive transfer of moDCs reverses the inhibitory effects of 5-FU treatment on Th2 cell responses in asthmatic mice. Surprisingly, 5-FU treatment does not suppress surface maturation markers and immunogenicity of moDCs in the lungs of asthmatic mice. Instead, it induces apoptotic cell death of mouse moDCs both in vitro and in vivo. In addition to its impact on mouse moDCs, we observe that low-dose 5-FU treatment can induce apoptotic cell death of human moDCs derived from peripheral blood mononuclear cells in vitro. Together, our findings reveal that low-dose 5-FU ameliorates Th2 cell responses, which may be at least partially related to the induction of apoptotic cell death of moDCs in asthma.


Assuntos
Asma , Monócitos , Humanos , Camundongos , Animais , Monócitos/patologia , Leucócitos Mononucleares/patologia , Asma/patologia , Células Th2 , Pulmão/patologia , Células Dendríticas/patologia , Apoptose , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico
18.
Food Funct ; 13(21): 10994-11007, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36239291

RESUMO

Natural polyphenols are plant metabolites exhibiting a broad range of biological activities. Among them, anticancer properties seem to be very desirable. This study examined the anticancer and anti-metastatic properties of the polyphenol-rich extract from the evening primrose seeds (EPE). In vitro and in vivo studies performed in colorectal cancer (CRC) cell lines and AOM-DSS-induced colitis-associated colon cancer in mice revealed the EPE anticancer properties. Furthermore, we studied the EPE activity on metastatic abilities and showed that the EPE inhibited invasiveness in the following models (cells isolated from patients with different invasive stages and cells with induced invasion by either Snail overexpression or CAF stimulation). More importantly, we also demonstrated that the EPE decreases the cell invasiveness of 5-fluorouracil (5-FU) resistant CRC cells. The inhibition of metastasis correlated with a decrease in thymidylate synthetase (TYMS), which has recently been associated with metastatic phenotype development. Our results indicate that the EPE might be an effective anticancer agent in suppressing colon cancer metastasis regardless of the invasiveness cause. Based on these findings, we concluded that the used EPE extract rich in polyphenols inhibits cell invasion by TYMS downregulation.


Assuntos
Neoplasias do Colo , Oenothera biennis , Camundongos , Animais , Timidilato Sintase/genética , Timidilato Sintase/metabolismo , Oenothera biennis/metabolismo , Polifenóis/farmacologia , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Extratos Vegetais/farmacologia
19.
Biomolecules ; 12(10)2022 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-36291699

RESUMO

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.


Assuntos
Antimaláricos , Antineoplásicos , Neoplasias da Mama , Neoplasias do Colo , Humanos , Feminino , Células MCF-7 , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antígeno Ki-67/metabolismo , Contenção de Riscos Biológicos , Tioridazina/farmacologia , Tioridazina/uso terapêutico , Artesunato/farmacologia , Artesunato/uso terapêutico , NF-kappa B/metabolismo , Flufenazina/farmacologia , Flufenazina/uso terapêutico , Benzotropina/farmacologia , Benzotropina/uso terapêutico , Sertralina/farmacologia , Sertralina/uso terapêutico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Michigan , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ribose/farmacologia , Ribose/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Paclitaxel/farmacologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Cloroquina/farmacologia , Difosfato de Adenosina , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral
20.
Eur J Pharm Biopharm ; 180: 224-237, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36220521

RESUMO

Three-dimensional cell culture systems are increasingly used for biological and anticancer drug screening as they mimic the structure and microenvironment of tumors more closely than conventional two-dimensional cell models. In this study, the growth kinetics of colon adenocarcinoma-derived spheroids (HT-29 cell line) cultivated in liquid marble micro-bioreactors and nonadherent PDMS-coated well plates was investigated in detail and enabled precise control of the spheroid size by the seed cell density and cultivation time. The therapeutic effect of 5-fluorouracil and irinotecan hydrochloride in 2D monolayer cell culture and 3D tumor spheroids revealed an unexpected twist in their efficacy due to different ability to penetrate through 3D microtissue. For 5-fluorouracil, the inhibitory concentration IC50 after 48 h exposure increased from 11.3 µM for a 2D cell culture to 707.7 µM for a 3D spheroid. In the case of irinotecan, IC50 increased from 24.9 µM to 77.8 µM. Despite its higher molar weight, irinotecan appeared to penetrate the 3D spheroid structure more efficiently than 5-fluorouracil. While 5-fluorouracil mainly caused a suppression of spheroid growth from the outside, irinotecan affected the entire spheroid and caused its originally compact structure to disintegrate. The acquired results highlight the need to screen cancer chemotherapeutics on 3D tumor models, as contrasting results can be obtained compared to standard 2D cell cultures.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Citostáticos , Humanos , Citostáticos/farmacologia , Irinotecano/farmacologia , Neoplasias do Colo/tratamento farmacológico , Esferoides Celulares , Fluoruracila/farmacologia , Linhagem Celular Tumoral , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...