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1.
Mater Sci Eng C Mater Biol Appl ; 127: 112238, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34225878

RESUMO

Fenton-based therapy is emerging as an effective and selective strategy against cancer. However, a low concentration of transition metal ions, insufficient endogenous H2O2, and a high level of antioxidant activity within the cancer cells have hindered the therapeutic efficacy of this strategy. To address these issues, in this study, the Fenton reagent (magnetic hydroxyapatite, mHAP) was accompanied with chemotherapy drugs (cisplatin (CDDP) and methotrexate (MTX)) and static magnetic field (SMF), in such a way to be a pH-, redox-, and magnetic-responsive nanoplatform. In vitro and in vivo experiments revealed higher toxicity of the final construct, MTX.CDDP@mHAP, toward colon cancer cells, as compared with that of free drugs. The most effective antitumor activity was observed as MTX.CDDP@mHAP-treated tumor cells were exposed to SMF (0.9 T) and no noticeable damage was observed in the normal cells and tissues. Active targeting by MTX and magnetic targeting by mHAP under magnetic field increased the tumor selectivity and enhanced the tumor site accumulation and cellular uptake of MTX.CDDP@mHAPs. The released iron ions within the cancer cells trigger the Fenton reaction while the release of chemotherapy drugs, reduction of intracellular glutathione, and application of SMF aggravated the Fenton reaction, subsequently leading to the generation of reactive oxygen species (ROS) and induction of apoptosis. Therefore, Fenton magnetic-based therapy-mediated by MTX.CDDP@mHAP could be considered as a promising strategy against colon cancer with high therapeutic efficiency and biosafety.


Assuntos
Antineoplásicos , Neoplasias do Colo , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Durapatita , Humanos , Campos Magnéticos , Fenômenos Magnéticos
2.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202689

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. One of its subtypes is associated with defective mismatch repair (dMMR) genes. Saffron has many potentially protective roles against colon malignancy. However, these roles in the context of dMMR tumors have not been explored. In this study, we aimed to investigate the effects of saffron and its constituents in CRC cell lines with dMMR. METHODS: Saffron crude extracts and specific compounds (safranal and crocin) were used in the human colorectal cancer cell lines HCT116, HCT116+3 (inserted MLH1), HCT116+5 (inserted MSH3), and HCT116+3+5 (inserted MLH1 and MSH3). CDC25b, p-H2AX, TPDP1, and GAPDH were analyzed by Western blot. Proliferation and cytotoxicity were analyzed by MTT. The scratch wound assay was also performed. RESULTS: Saffron crude extracts restricted (up to 70%) the proliferation in colon cells with deficient MMR (HCT116) compared to proficient MMR. The wound healing assay indicates that deficient MMR cells are doing better (up to 90%) than proficient MMR cells when treated with saffron. CDC25b and TDP1 downregulated (up to 20-fold) in proficient MMR cells compared to deficient MMR cells, while p.H2AX was significantly upregulated in both cell types, particularly at >10 mg/mL saffron in a concentration-dependent manner. The reduction in cellular proliferation was accompanied with upregulation of caspase 3 and 7. The major active saffron compounds, safranal and crocin reproduced most of the saffron crude extracts' effects. CONCLUSIONS: Saffron's anti-proliferative effect is significant in cells with deficient MMR. This novel effect may have therapeutic implications and benefits for MSI CRC patients who are generally not recommended for the 5-fluorouracil-based treatment.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Crocus/química , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Instabilidade de Microssatélites/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Extratos Vegetais/química
3.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299028

RESUMO

Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antipsicóticos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Sinergismo Farmacológico , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasias do Colo/patologia , Quimioterapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas
4.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201061

RESUMO

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mutação , Proteínas Nucleares/metabolismo , Proteoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Vemurafenib/farmacologia , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Proteoma/análise , Células Tumorais Cultivadas
5.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069111

RESUMO

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.


Assuntos
Antiparasitários/farmacologia , Neoplasias do Colo/tratamento farmacológico , Nitrocompostos/farmacologia , Tiazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antiparasitários/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HCT116 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nitrocompostos/química , Antígeno Nuclear de Célula em Proliferação/imunologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Tiazóis/química , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
6.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071597

RESUMO

In the search of new natural products to be explored as possible anticancer drugs, two plant species, namely Ononis diffusa and Ononis variegata, were screened against colorectal cancer cell lines. The cytotoxic activity of the crude extracts was tested on a panel of colon cancer cell models including cetuximab-sensitive (Caco-2, GEO, SW48), intrinsic (HT-29 and HCT-116), and acquired (GEO-CR, SW48-CR) cetuximab-resistant cell lines. Ononis diffusa showed remarkable cytotoxic activity, especially on the cetuximab-resistant cell lines. The active extract composition was determined by NMR analysis. Given its complexity, a partial purification was then carried out. The fractions obtained were again tested for their biological activity and their metabolite content was determined by 1D and 2D NMR analysis. The study led to the identification of a fraction enriched in oxylipins that showed a 92% growth inhibition of the HT-29 cell line at a concentration of 50 µg/mL.


Assuntos
Cetuximab/farmacologia , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Espectroscopia de Ressonância Magnética/métodos , Ononis/metabolismo , Extratos Vegetais/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Desenho de Fármacos , Células HCT116 , Células HT29 , Humanos , Oxilipinas/química , Fitoterapia/métodos , Especificidade da Espécie
7.
Ann Agric Environ Med ; 28(2): 291-299, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34184513

RESUMO

INTRODUCTION: Due to the fact that lymphocytes NK (natural killer cells) are the first line of defence of the body against cancer, one of the goals of modern immunotherapy is the enhancement of their natural activities for the effective recognition, detection, and elimination of cancer cells. OBJECTIVE: The aim of the study was to evaluate the influence of selected phytochemicals (curcumin and resveratrol) and plant extracts (chlorella and goji berries) on NK cells viability and proliferation, as well as cytotoxic activity against colon cancer - one of the most common cancer worldwide. MATERIAL AND METHODS: The impact of phytochemicals, viability and proliferation of plant extracts on NK cells was examined in NK-92 cells using both LDH and MTT assays. The immunomodulatory properties of selected compounds were tested against human colon cancer cell line LS180 using the MTT test. RESULTS: Extracts of chlorella and goji berries significantly increased NK cell proliferation, while curcumin and resveratrol did not affect this process. Curcumin, as well as extracts of chlorella and goji berries, did not impact NK viability, while resveratrol significantly increased it. LDH test revealed the cytotoxic effect of chlorella extract and curcumin in NK-92 cell cultures. On the contrary, goji berries extract significantly decreased LDH level, while resveratrol did not affect the integrity of NK cell membranes. Studies conducted in co-cultures NK cells, also directly eliminated colon cancer cells. CONCLUSIONS: Performed studies revealed immunomodulatory properties of goji berries extract, which improved viability and proliferation of NK cells, and above all, significantly increased their ability to recognize and eliminate colon cancer cells.


Assuntos
Neoplasias do Colo/fisiopatologia , Curcumina/farmacologia , Fatores Imunológicos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Lycium/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Resveratrol/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorella/química , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Frutas/química , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia
8.
J Int Med Res ; 49(6): 3000605211017037, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34082600

RESUMO

Primary colonic lymphoma is a very rare malignant tumor with no standard treatment. We report two cases of primary colonic lymphoma successfully treated with surgery and chemotherapy, and chemotherapy alone, respectively. The first case was a 61-year-old woman who presented with abdominal pain of more than 1 month. The patient was diagnosed with a colonic tumor, and immunohistochemical examinations confirmed the initial diagnosis of colonic lymphoma. The patient underwent laparoscopic-assisted right hemicolectomy followed by postoperative adjuvant chemotherapy with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen, combined with targeted therapy with rituximab (R-CHOP). The second case was a 78-year-old man who presented with a complaint of abdominal distention for more than 1 year. Diffuse large B-cell lymphoma was definitively diagnosed by immunohistochemical examinations, and the patient underwent systemic chemotherapy with the R-CHOP regimen. Primary colonic lymphoma is a rare type of non-Hodgkin's lymphoma (NHL), and the clinical treatment is not standardized, unlike for many other types of lymphoma. Therefore, treatment is mainly based on the patient's symptoms to determine whether surgery or systemic chemotherapy is appropriate. Rituximab is effective in some patients and may play an important role in the treatment of unresectable or asymptomatic colonic lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Colo , Idoso , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
9.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070303

RESUMO

Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias do Colo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Animais , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Eur J Pharm Sci ; 163: 105864, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33965502

RESUMO

BACKGROUND: Oxaliplatin (OXE) combined with other chemotherapy drugs against colorectal cancer had been reported in the literature before, however, the efficacy of oxaliplatin combined with natural compounds was elusive. In addition, the clinical bioactivity and therapeutic dose of antitumor drugs are severely limited due to poor targeting and side effects. NDDSs offers an excellent strategy to overcome the disadvantages of small molecule anticancer drugs. METHODS: Here, we have prepared N,O-carboxymethyl chitosan Oxaliplatin nanoparticles (CMCS-OXE NPs) and N,O-carboxymethyl chitosan Resveratrol nanoparticles (CMCS-Res NPs) were prepared by ion crosslinking and emulsification crosslinking, respectively. RESULTS: The results revealed that the CMCS-OXE NPs exhibited a high encapsulation efficiency (60%) with a size of approximately 190.0 nm, and the CMCS-Res NPs exhibited a high encapsulation efficiency (65%) with a size of approximately 164.2 nm. The treatment with both types of nanoparticles combined exhibited more significant anti-colon cancer activity than the free drugs or either type of nanoparticle alone. In the in vivo experiments, the inhibition efficiency of the combined nanoparticle treatment was much stronger than the free drugs or either type of nanoparticle alone. CONCLUSIONS: Overall, combination of oxaliplatin and resveratrol into a nanoparticle-drug delivery systems (NDDSs) appears to be a promising strategy for colorectal cancer (CRC) therapy.


Assuntos
Quitosana , Neoplasias do Colo , Nanopartículas , Quitosana/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Portadores de Fármacos/uso terapêutico , Humanos , Oxaliplatina , Resveratrol
12.
Zhongguo Zhong Yao Za Zhi ; 46(9): 2267-2275, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34047130

RESUMO

Astragali Radix-Curcumae Rhizoma is a classic drug pair mainly used for the treatment of digestive tract-related inflammation and tumors, but the ratio is not fixed in clinical practice. In order to study whether the anti-tumor effect of the drug pair is diffe-rent under different ratios, orthotopic transplantation model of colon cancer was established in mice. Then the principal component analysis(PCA) and cluster analysis(CA) were used to explore the effect of different ratios of the drug pair on the tumor growth and metastasis, and select the optimal ratio of Astragali Radix-Curcumae Rhizoma for anti-colon cancer effect. After administration for 15 days, the body weight of colon cancer mice with the tumor removed, the tumor volume and the number of liver metastases were mea-sured; the pathological changes of tumor tissue and liver tissue were observed by HE staining. At the same time, Western blot method was used to detect the protein expression level of tumor growth-related indicators in tumor tissue(Ki67, HBP1, AFP) and tumor metastasis-related indicators in liver tissue(ß-catenin, E-cadherin, vimentin, p53) of the tumor-bearing mice. Subsequently, PCA and CA were used to select the optimal ratio of Astragali Radix-Curcumae Rhizoma for anti-colon cancer effect. The experimental results showed that different ratios of Astragali Radix-Curcumae Rhizoma inhibited tumor growth and metastasis to varying degrees. The ratio at 1∶1 of Astragali Radix-Curcumae Rhizoma had the best inhibitory effect on tumor growth, and the 2∶1 ratio group had the best effect on inhibiting liver metastasis and improving weighed loss. Astragali Radix-Curcumae Rhizoma significantly up-regulated the protein expression of HBP1 in tumor tissue of colon cancer mice, and significantly down-regulated the protein expression of Ki67 and AFP in tumor tissue; meanwhile, Astragali Radix-Curcumae Rhizoma significantly up-regulated the protein expression of E-cadherin in liver tissue of colon cancer mice, and significantly reduced the protein expression of ß-catenin, vimentin and p53 in liver tissue. PCA results showed that the first three groups in the Astragali Radix-Curcumae Rhizoma compatibility group that were closer to the sham operation group were in the order of 2∶1, 1∶1 and 3∶2, among which the center distance of the 2∶1 group was the shortest from the sham operation group, indicating that the ratio 2∶1 of Astragali Radix-Curcumae Rhizoma had the best intervention effect on colon cancer in mice, consistent with the commonly used clinical proportion. CA results showed that 11 groups of colon cancer mice were classified into 3 categories: Astragali Radix-Curcumae Rhizoma compatibility group, sham operation group and model group, which was consistent with the theory. The results of this study provide a basis for more effective clinical application of Astragali Radix-Curcumae Rhizoma in the treatment of colon cancer, and provide new ideas for the development of classic drug pairs.


Assuntos
Astrágalo (Planta) , Neoplasias do Colo , Medicamentos de Ervas Chinesas , Animais , Neoplasias do Colo/tratamento farmacológico , Camundongos , Raízes de Plantas , Rizoma
13.
BMJ Case Rep ; 14(5)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972305

RESUMO

Multiple primaries in patients with prostate cancer are uncommon. We report a case of prostate adenocarcinoma who did not receive any form of treatment, diagnosed 7 months later with colon adenocarcinoma. The patient underwent right extended hemicolectomy and recovered well. He is planned to receive adjuvant chemotherapy and hormonal therapy. Management of such cases can present a dilemma and multiple factors must be taken into consideration, particularly when the first primary tumour is still active.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Neoplasias da Próstata , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Neoplasias do Colo/tratamento farmacológico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico
14.
Medicine (Baltimore) ; 100(21): e26068, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032736

RESUMO

ABSTRACT: Some patients with advanced colon adenocarcinoma (COAD) are not sensitive to radiotherapy and chemotherapy, and as such, immunotherapy has become the most popular option for these patients. However, different patients respond differently to immunotherapy. Tumor mutational burden (TMB) has been used as a predictor of the response of advanced COAD patients to immunotherapy. A high TMB typically indicates that the patient's immune system will respond well to immunotherapy. In addition, while microRNAs (miRNA) have been shown to play an important role in treatment responses associated with the immune system, the relationship between miRNA expression levels and TMB has not been clarified in COAD.We downloaded miRNA data and mutational files of COAD from the Cancer Genome Atlas database. Differentially expressed miRNAs were screened in the training group, and miRNAs used to construct the model were further identified using the LASSO logistic regression method. After building the miRNA-based model, we explored the correlation between the model and TMB. The model was verified by a receiver operating characteristic curve, and the correlation between it and 3 widely used immune checkpoints (programmed death receptor-1, programmed death-ligand 1, and cytotoxic T-lymphocyte associated protein-4) was explored. Functional enrichment analysis of the selected miRNAs was performed, and these respective miRNA target genes were predicted using online tools.Our results showed that a total of 32 differentially expressed miRNAs were used in the construction of the model. The accuracies of the models of the 2 datasets (training and test sets) were 0.987 and 0.934, respectively. Correlation analysis showed that the correlation of the model with programmed death-ligand 1 and cytotoxic T-lymphocyte associated protein-4, as well as TMB, was high, but there was no correlation with programmed death receptor-1. The results of functional enrichment analysis indicated that these 32 miRNAs were involved in many immune-related biological processes and tumor-related pathways.Therefore, this study demonstrated that differentially expressed miRNAs can be used to predict the TMB level, which can help identify advanced COAD patients who will respond well to immunotherapy. The miRNA-based model may be used as a tool to predict the TMB level in patients with advanced COAD.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/genética , MicroRNAs/metabolismo , Modelos Genéticos , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Logísticos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Curva ROC , Tolerância a Radiação/genética
15.
J Pharm Biomed Anal ; 201: 114129, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000577

RESUMO

Doxorubicin (Dox) is commonly used for the treatment of malignant tumors, including colon cancer. However, the development of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor chemotherapy has seriously reduced the therapeutic efficacy of Dox. Natural product curcumin (Cur) was demonstrated to have a variety of pharmacological effects, such as anti-tumor, anti-oxidation and anti-aging activities. Here, we examined the MDR reversal capability of Cur in drug sensitive-(SW620) and resistant-(SW620/Ad300) colon cancer cells, and elucidated the underlying molecular mechanisms at the metabolic level. It was found that Cur reversed P-gp-mediated resistance in SW620/Ad300 cells by enhancing the Dox-induced cytotoxicity and apoptosis. Further mechanistic studies indicated that Cur inhibited the ATP-dependent transport activity of P-gp, thereby increasing the intra-celluar accumulation of Dox in drug-resistant cells. Metabolomics analysis based on UPLC-MS/MS showed that the MDR phenomenon in SW620/Ad300 cells was closely correlated with the upregulation of spermine and spermidine synthesis and D-glutamine metabolism. Cur significantly inhibited the biosynthesis of spermine and spermidine by decreasing the expression of ornithine decarboxylase (ODC) and suppressed D-glutamine metabolism, which in turn decreased the anti-oxidative stress ability and P-gp transport activity of SW620/Ad300 cells, eventually reversed MDR. These findings indicated the MDR reversal activity and the related mechanism of action of Cur, suggesting that Cur could be a promising MDR reversal agent for cancer treatment.


Assuntos
Neoplasias do Colo , Curcumina , Linhagem Celular Tumoral , Cromatografia Líquida , Neoplasias do Colo/tratamento farmacológico , Curcumina/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Espectrometria de Massas em Tandem
16.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922320

RESUMO

A high rate of glycolysis is considered a hallmark of tumor progression and is caused by overexpression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Therefore, we analyzed the possibility of inhibiting tumor and endothelial cell metabolism through the inhibition of PFKFB3 by a small molecule, (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15), as a promising therapy. The effects of PFK15 on cell proliferation and apoptosis were analyzed on human umbilical vein endothelial cells (HUVEC) and the human colorectal adenocarcinoma cell line DLD1 through cytotoxicity and proliferation assays, flow cytometry, and western blotting. The results showed that PFK15 inhibited the proliferation of both cell types and induced apoptosis with decreasing the Bcl-2/Bax ratio. On the basis of the results obtained from in vitro experiments, we performed a study on immunodeficient mice implanted with DLD1 cells. We found a reduced tumor mass after morning PFK15 treatment but not after evening treatment, suggesting circadian control of underlying processes. The reduction in tumor size was related to decreased expression of Ki-67, a marker of cell proliferation. We conclude that inhibition of glycolysis can represent a promising therapeutic strategy for cancer treatment and its efficiency is circadian dependent.


Assuntos
Cronoterapia/métodos , Neoplasias do Colo/tratamento farmacológico , Glucose/metabolismo , Glicólise , Fosfofrutoquinase-2/antagonistas & inibidores , Piridinas/farmacologia , Quinolinas/farmacologia , Animais , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
FASEB J ; 35(5): e21432, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33794029

RESUMO

While failure in resolution of inflammation is considered to increase the risk of tumorigenesis, there is paucity of experimental as well as clinical evidence supporting this association. Resolvin D1 (RvD1) is a representative pro-resolving lipid mediator that is endogenously generated from docosahexaenoic acid for the resolution of inflammation. Here, we report a decreased level of RvD1 in the blood from colorectal cancer patients and mice having inflammation-induced colon cancer, suggesting plasma RvD1 as a potential biomarker for monitoring colorectal cancer. Administration of RvD1 attenuated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colorectal carcinogenesis by suppressing the production of interleukin-6 (IL-6) and IL-6-mediated chromosomal instability. The protective effect of RvD1 against chromosomal instability is associated with downregulation of IL-6-induced Cyclin D1 expression, which appears to be mediated by blocking the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) axis. RvD1 inhibited the STAT3 signaling pathway by interfering with the binding of IL-6 to its receptor (IL-6R), suggesting the novel function of RvD1 as a putative IL-6R antagonist. Together, our findings suggest that RvD1-mediated blockade of IL-6 signal transmission may contribute to inhibition of chromosomal instability and tumorigenesis.


Assuntos
Carcinogênese/patologia , Colite/complicações , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-6/farmacologia , Fuso Acromático/efeitos dos fármacos , Animais , Carcinogênese/metabolismo , Estudos de Casos e Controles , Colite/induzido quimicamente , Colite/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fuso Acromático/patologia
18.
Food Funct ; 12(8): 3527-3538, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900335

RESUMO

This study explored the effects of lotus seedpod oligomeric procyanidins (LSOPC) and their main monomer catechin (CC) on the formation of advanced glycation end products (AGEs) and Caco-2 cytotoxicity during gastrointestinal digestion. Studies have found that LSOPC and CC inhibited the AGEs formation effectively in simulated gastrointestinal digestion and protected Caco-2 cells from AGEs attack. The effect of CC on the inhibition of AGEs formation was significantly better than that of LSOPC. Further, they could effectively inhibit the digestive enzyme activity, reactive oxygen species, RAGE-p38MAPK-NF-κB signaling pathway, inflammatory factors (tumor necrosis factor alpha, interleukin 6), and adhesion factors (intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1) to protect Caco-2 cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Trato Gastrointestinal/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Nelumbo/química , Proantocianidinas/farmacologia , Sementes/química , Apoptose/efeitos dos fármacos , Células CACO-2 , Catequina/farmacologia , Neoplasias do Colo/tratamento farmacológico , Digestão , Trato Gastrointestinal/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Pepsina A/antagonistas & inibidores , Espécies Reativas de Oxigênio/análise , Tocoferóis/análise , Inibidores da Tripsina/farmacologia
19.
JAMA ; 325(13): 1277-1286, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33821899

RESUMO

Importance: Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown. Objective: To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer. Design, Setting, and Participants: Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020. Interventions: Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization. Main Outcomes and Measures: The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events. Results: Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively. Conclusions and Relevance: Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Celecoxib/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Celecoxib/efeitos adversos , Neoplasias do Colo/cirurgia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Cooperação do Paciente , Modelos de Riscos Proporcionais , Prevenção Secundária , Taxa de Sobrevida , Falha de Tratamento , Adulto Jovem
20.
Gene ; 786: 145625, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-33798683

RESUMO

BACKGROUND: Mounting evidences suggested that anlotinib exhibits effective anti-tumor activity in various cancer types, such as lung cancer, glioblastoma and medullary thyroid cancer. However, its function in colon cancer remains to be further revealed. METHODS: Colon cancer cells (HCT-116) were treated with or without anlotinib. Transcript and metabolite data were generated through RNA sequencing and liquid chromatography-tandem mass spectrometry, respectively. The integrated analysis transcriptomics and metabolomics was conducted using R programs and online tools, including ClusterProfiler R program, GSEA, Prognoscan and Cytoscape. RESULTS: We found that differentially expressed genes (DEGs) were mainly involved in metabolic pathways and ribosome pathway. Structural maintenance of chromosome 3 (SMC3), Topoisomerase II alpha (TOP2A) and Glycogen phosphorylase B (PYGB) are the most significant DEGs which bring poor clinical prognosis in colon cancer. The analysis of metabolomics presented that most of the differentially accumulated metabolites (DAMs) were amino acids, such as L-glutamine, DL-serine and aspartic acid. The joint analysis of DEGs and DAMs showed that they were mainly involved in protein digestion and absorption, ABC transporters, central carbon metabolism, choline metabolism and Gap junction. Anlotinib affected protein synthesis and energy supporting of colon cancer cells by regulating amino acid metabolism. CONCLUSIONS: Anlotinib has a significant effect on colon cancer in both transcriptome and metabolome. Our research will provide possible targets for colon cancer treatment using anlotinib.


Assuntos
Neoplasias do Colo/genética , Perfilação da Expressão Gênica/métodos , Indóis/farmacologia , Metabolômica/métodos , Quinolinas/farmacologia , Ácido Aspártico/metabolismo , Proteínas de Ciclo Celular/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Cromatografia Líquida , Proteínas Cromossômicas não Histona/genética , Neoplasias do Colo/química , Neoplasias do Colo/tratamento farmacológico , DNA Topoisomerases Tipo II/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Glutamina/metabolismo , Glicogênio Fosforilase/genética , Células HCT116 , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Análise de Sequência de RNA , Espectrometria de Massas em Tandem
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