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1.
J Ethnopharmacol ; 330: 118195, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38641080

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is a frequently used herbal medicine worldwide, and is used to treat cough, hepatitis, cancer and influenza in clinical practice of traditional Chinese medicine. Modern pharmacological studies indicate that prenylated flavonoids play an important role in the anti-tumor activity of licorice, especially the tumors in stomach, lung, colon and liver. Wighteone is one of the main prenylated flavonoids in licorice, and its possible effect and target against colorectal cancer have not been investigated. AIM OF THE STUDY: This study aimed to investigate the anti-colorectal cancer effect and underlying mechanism of wighteone. MATERIALS AND METHODS: SW480 human colorectal cancer cells were used to evaluate the in vitro anti-colorectal cancer activity and Akt regulation effect of wighteone by flow cytometry, phosphoproteomic and Western blot analysis. Surface plasmon resonance (SPR) assay, molecular docking and dynamics simulation, and kinase activity assay were used to investigate the direct interaction between wighteone and Akt. A nude mouse xenograft model with SW480 cells was used to verify the in vivo anti-colorectal cancer activity of wighteone. RESULTS: Wighteone inhibited phosphorylation of Akt and its downstream kinases in SW480 cells, which led to a reduction in cell viability. Wighteone had direct interaction with both PH and kinase domains of Akt, which locked Akt in a "closed" conformation with allosteric inhibition, and Gln79, Tyr272, Arg273 and Lys297 played the most critical role due to their hydrogen bond and hydrophobic interactions with wighteone. Based on Akt overexpression or activation in SW480 cells, further mechanistic studies suggested that wighteone-induced Akt inhibition led to cycle arrest, apoptosis and autophagic death of SW480 cells. Moreover, wighteone exerted in vivo anti-colorectal cancer effect and Akt inhibition activity in the nude mouse xenograft model. CONCLUSION: Wighteone could inhibit growth of SW480 cells through allosteric inhibition of Akt, which led to cell cycle arrest, apoptosis and autophagic death. The results contributed to understanding of the anti-tumor mechanism of licorice, and also provided a rationale to design novel Akt allosteric inhibitors for the treatment of colorectal cancer.


Asunto(s)
Antineoplásicos Fitogénicos , Neoplasias Colorrectales , Flavonoides , Glycyrrhiza , Proteínas Proto-Oncogénicas c-akt , Animales , Humanos , Masculino , Ratones , Regulación Alostérica/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/uso terapéutico , Flavonoides/química , Glycyrrhiza/química , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Zhongguo Zhong Yao Za Zhi ; 49(6): 1455-1466, 2024 Mar.
Artículo en Chino | MEDLINE | ID: mdl-38621929

RESUMEN

Ulcerative colitis is a chronic, recurrent, and nonspecific intestinal inflammatory disease, which is difficult to cure and has the risk of deterioration into related tumors. Long-term chronic inflammatory stimulation can increase the risk of cancerization. With the signaling pathway as a key link in the regulation of tumor microenvironments, nuclear factor-kappa B(NF-κB) is an important regulator of intestinal inflammation. It can also be co-regulated as downstream factors of other signaling pathways, such as TLR4, MAPK, STAT, PI3K, and so on. At present, a large number of animal experiments have proved that traditional Chinese medicine(TCM) can reduce inflammation by interfering with NF-κB-related signaling pathways, improve intestinal inflammation, and inhibit the progression of inflammation to tumors. This article reviewed the relationship between NF-κB-related signaling pathways and the intervention mechanism of TCM, so as to provide a reference for the clinical treatment of ulcerative colitis and the optimization of related cancer prevention strategies.


Asunto(s)
Colitis Ulcerosa , Neoplasias Colorrectales , Animales , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Modelos Animales de Enfermedad , Inflamación , Medicina Tradicional China , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal , Microambiente Tumoral
3.
Phytomedicine ; 128: 155497, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38640855

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is a significant public health issue, ranking as one of the predominant cancer types globally in terms of incidence. Intriguingly, Arenobufagin (Are), a compound extracted from toad venom, has demonstrated the potential to inhibit tumor growth effectively. PURPOSE: This study aimed to explore Are's molecular targets and unravel its antitumor mechanism in CRC. Specifically, we were interested in its impact on immune checkpoint modulation and correlations with HSP90ß-STAT3-PD-L1 axis activity. METHODS: We investigated the in vivo antitumor effects of Are by constructing a colorectalcancer subcutaneous xenograft mouse model. Subsequently, we employed single-cell multi-omics technology to study the potential mechanism by which Are inhibits CRC. Utilizing target-responsive accessibility profiling (TRAP) technology, we identified heatshock protein 90ß (HSP90ß) as the direct target of Are, and confirmed this through a microscale thermophoresis experiment (MST). Further downstream mechanisms were explored through techniques such as co-immunoprecipitation, Western blotting, qPCR, and immunofluorescence. Concurrently, we arrived at the same research conclusion at the organoid level by co-cultivating with immune cells. RESULTS: We observed that Are inhibits PD-Ll expression in CRC tumor xenografts at low concentrations. Moreover, TRAP revealed that HSP90ß's accessibility significantly decreased upon Are binding. We demonstrated a decrease in the activity of the HSP90ß-STAT3-PD-Ll axis following low-concentration Are treatment in vivo. The PDO analysis showed improved enrichment of lymphocytes, particularly T cells, on the PDOs following Are treatment. CONCLUSION: Contrary to previous research focusing on the direct cytotoxicity of Are towards tumor cells, our findings indicate that it can also inhibit tumor growth at lower concentrations through the modulation of immune checkpoints. This study unveils a novel anti-tumor mechanism of Are and stimulates contemplation on the dose-response relationship of natural products, which is beneficial for the clinical translational application of Are.


Asunto(s)
Bufanólidos , Neoplasias Colorrectales , Proteínas HSP90 de Choque Térmico , Factor de Transcripción STAT3 , Ensayos Antitumor por Modelo de Xenoinjerto , Bufanólidos/farmacología , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Ratones , Factor de Transcripción STAT3/metabolismo , Linfocitos T/efectos de los fármacos , Línea Celular Tumoral , Antígeno B7-H1 , Ratones Desnudos , Ratones Endogámicos BALB C , Venenos de Anfibios/farmacología , Femenino
4.
Phytomedicine ; 128: 155385, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38569292

RESUMEN

BACKGROUND: Xianlian Jiedu Decoction (XLJDD) has been used for the treatment of colorectal cancer (CRC) for several decades because of the prominent efficacy of the prescription. Despite the clear clinical efficacy of XLJDD, the anti-CRC mechanism of action is still unclear. PURPOSE: The inhibitory effect and mechanism of XLJDD on CRC were investigated in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mice. METHODS: The AOM/DSS-induced mice model was adopted to evaluate the efficacy after administering the different doses of XLJDD. The therapeutic effects of XLJDD in treating AOM/DSS-induced CRC were investigated through histopathology, immunofluorescence and ELISA analysis methods. In addition, metabolomics profile and 16S rRNA analysis were used to explore the effective mechanisms of XLJDD on CRC. RESULTS: The results stated that the XLJDD reduced the number of tumor growth on the inner wall of the colon and the colorectal weight/length ratio, and suppressed the disease activity index (DAI) score, meanwhile XLJDD also increased body weight, colorectal length, and overall survival rate. The treatment of XLJDD also exhibited the ability to lower the level of inflammatory cytokines in serum and reduce the expression levels of ß-catenin, COX-2, and iNOS protein in colorectal tissue. The findings suggested that XLJDD has anti-inflammatory properties and may provide relief for those suffering from inflammation-related conditions. Mechanistically, XLJDD improved gut microbiota dysbiosis and associated metabolic levels of short chain fatty acids (SCFAs), sphingolipid, and glycerophospholipid. This was achieved by reducing the abundance of Turicibacter, Clostridium_sensu_stricto_1, and the levels of sphinganine, LPCs, and PCs. Additionally, XLJDD increased the abundance of Enterorhabdus and Alistipes probiotics, as well as the content of butyric acid and isovaleric acid. CONCLUSION: The data presented in this article demonstrated that XLJDD can effectively inhibit the occurrence of colon inner wall tumors by reducing the level of inflammation and alleviating intestinal microbial flora imbalance and metabolic disorders. It provides a scientific basis for clinical prevention and treatment of CRC.


Asunto(s)
Azoximetano , Neoplasias Colorrectales , Sulfato de Dextran , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Ratones , Masculino , Modelos Animales de Enfermedad , Metaboloma/efectos de los fármacos , Colon/efectos de los fármacos , Colon/patología , Colon/microbiología
5.
J Gastrointest Surg ; 28(4): 425-433, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38583892

RESUMEN

PURPOSE: This study aimed to analyze the clinical effect of simultaneous resection of liver metastases combined with hyperthermic intraperitoneal chemotherapy (HIPEC) on synchronous colorectal cancer liver metastasis. METHODS: A total of 144 patients with synchronous colorectal cancer liver metastasis who were admitted to our hospital between January 2018 and January 2019 were randomly assigned into a control group and an intervention group. The patients in the control group received simultaneous resection of liver metastases. The patients in the intervention group obtained simultaneous resection of liver metastases combined with HIPEC. The recent total effective rate of the 2 groups was compared, and the disease control rate of the 2 groups was calculated at 3 months after treatment. The patients were followed up for 3 years. The survival time of the 2 groups was observed and compared. Fasting venous blood was collected from patients in the 2 groups, and the carcinoembryonic antigen (CEA) level was compared. The level of quality of life scale (Short Form 36-item Health Survey) and the occurrence of adverse reactions were compared between the 2 groups. RESULTS: The R0 complete resection rate in the intervention group was significantly higher than that in the control group (P < .05). The recent total effective rate in the intervention group (87.50%) was significantly higher than that in the control group (59.72%) (P < .05). The negative change of CEA in the intervention group was 72.22%, which was prominently higher than that in the control group of 43.06% (χ2 = 12.542, P < .001). After a 36-month follow-up, the overall survival rate of the observation group was significantly higher than that of the control group (hazard ratio, 2.54; 95% CI, 1.05-5.48; P < .001). The patients in the intervention group had significantly higher life quality scores of health status, social function, emotional function, physical function, and mental health than in the control group (P < .05). There was no significant difference in the incidence of complications between the 2 groups (P > .05). Age > 60 years, preoperative comorbidities, moderate and high differentiation of tumors, intraoperative blood loss > 150 mL, and less experienced surgeons were risk factors affecting the occurrence of complications after treatment and were closely correlated with the prognosis and survival of patients (P < .05). Patients with age ≤ 60 years, no preoperative comorbidities, low tumor differentiation, intraoperative blood loss ≤ 150 mL, more experienced surgeons, and complete R0 resection had a longer survival time. Age > 60 years, preoperative comorbidities, moderate and high differentiation of tumors, intraoperative blood loss > 150 mL, and less experienced surgeons were independent risk factors affecting the prognosis of patients with colorectal cancer liver metastases (P < .05), whereas R0 surgery was an independent protective factor for the prognosis (P < .05). CONCLUSION: In the treatment of synchronous colorectal cancer liver metastases, simultaneous resection of liver metastases in conjunction with HIPEC demonstrated superior efficacy. This approach may potentially extend patient survival and enhance quality of life and deserve to be extensively used in clinical practice.


Asunto(s)
Neoplasias Colorrectales , Hipertermia Inducida , Neoplasias Hepáticas , Humanos , Persona de Mediana Edad , Quimioterapia Intraperitoneal Hipertérmica , Antígeno Carcinoembrionario , Pérdida de Sangre Quirúrgica , Calidad de Vida , Neoplasias Colorrectales/cirugía , Hepatectomía , Estudios Retrospectivos , Terapia Combinada , Neoplasias Hepáticas/cirugía , Tasa de Supervivencia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
6.
Chin J Nat Med ; 22(4): 329-340, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658096

RESUMEN

The management of colorectal cancer (CRC) poses a significant challenge, necessitating the development of innovative and effective therapeutics. Our research has shown that notoginsenoside Ft1 (Ng-Ft1), a small molecule, markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8+ T cells in tumor-bearing mice, thus restraining tumor growth. Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X, undermining its role in shielding ß-catenin. This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway. These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC, working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8+ T cell prevalence within the tumor environment.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias Colorrectales , Ubiquitina Tiolesterasa , Vía de Señalización Wnt , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Ratones , Humanos , Vía de Señalización Wnt/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , beta Catenina/metabolismo , Ratones Endogámicos BALB C
7.
Chin J Nat Med ; 22(4): 318-328, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658095

RESUMEN

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1ß inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein's specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.


Asunto(s)
Antraquinonas , Proliferación Celular , Neoplasias Colorrectales , Quinasas Similares a Doblecortina , Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Factor de Transcripción STAT3 , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Antraquinonas/farmacología , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos
8.
J Ethnopharmacol ; 331: 118213, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-38636576

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The sclerotium of Lignosus rhinocerus (Cooke) Ryvarden is used by the local communities in Southeast Asia and China to treat cancer, asthma, fever, and other ailments based on traditional knowledge. The sclerotial water extracts were previously reported to exhibit cytotoxic, apoptotic, and immunomodulatory activities - providing a scientific basis for its use in treating cancer; however, there is still a lack of evidence on its potential anti-angiogenic activity. AIM OF THE STUDY: This study aimed to investigate the toxicity, anti-angiogenic, and anti-tumour activities of the hot-water and cold-water extracts of L. rhinocerus using HCT116 human colorectal carcinoma cells implanted in the chick chorioallantoic membrane (CAM) model. MATERIALS AND METHODS: The toxicity of L. rhinocerus extracts towards the chick embryos was determined 24 h post-treatment. The anti-angiogenic activity of the extracts was then investigated at 0.1-10 µg/embryo (6.7-670 µg/mL) at targeted blood vessels. The anti-tumour effect of selected extracts against the HCT116 human colorectal carcinoma cells xenografted onto the chick embryos was also studied. RESULTS: The cold-water extracts of L. rhinocerus displayed strong in ovo toxicity (LC50: 1.2-37.7 µg/mL) while the hot-water extracts are non-toxic up to 670 µg/mL. Among the extracts, the hot-water extracts demonstrated the highest anti-angiogenic activity with 44.0 ± 17.7% reduction of capillary diameter (relative to the saline-treated control). Moreover, treatment of the HCT116 cells xenografted onto the chick embryos with the hot-water extracts resulted in smaller tumour size and lower number of blood vessels compared to the saline-treated control. CONCLUSIONS: The hot-water extracts of L. rhinocerus sclerotium demonstrated anti-angiogenic and anti-tumour activities but most of the cold-water extracts at similar concentrations were devoid of that. Our findings provide further scientific validation of the medicinal use of the sclerotium in treating cancer and thus, expanding our knowledge on the possible mechanism of its anti-cancer effect apart from direct cytotoxicity, induction of apoptosis and immunomodulation that have been studied thus far.


Asunto(s)
Inhibidores de la Angiogénesis , Membrana Corioalantoides , Neoplasias Colorrectales , Animales , Embrión de Pollo , Humanos , Células HCT116 , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/irrigación sanguínea , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Agua/química , Antineoplásicos Fitogénicos/farmacología , Polyporaceae/química
9.
Med Oncol ; 41(5): 123, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38652404

RESUMEN

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.


Asunto(s)
Apoptosis , Benzoquinonas , Supervivencia Celular , Neoplasias Colorrectales , Maleato de Dizocilpina , Mitocondrias , Receptores de N-Metil-D-Aspartato , Humanos , Benzoquinonas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Células HT29 , Maleato de Dizocilpina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Supervivencia Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos
10.
Chin J Integr Med ; 30(6): 565-576, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38565799

RESUMEN

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.


Asunto(s)
Neoplasias Asociadas a Colitis , Progresión de la Enfermedad , Macrófagos , Humanos , Macrófagos/patología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Colorrectales/patología , Animales , Colitis Ulcerosa/patología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/complicaciones
11.
Phytomedicine ; 129: 155615, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38615493

RESUMEN

BACKGROUND: Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor. PURPOSE: Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis. STUDY DESIGN: A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model. METHODS: MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence. RESULTS: GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA). CONCLUSION: CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.


Asunto(s)
Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Ratones , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Células HCT116 , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Masculino , Serina-Treonina Quinasas TOR/metabolismo
12.
JAMA Netw Open ; 7(4): e245295, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38625704

RESUMEN

Importance: Organized screening outreach can reduce differences in colorectal cancer (CRC) incidence and mortality between demographic subgroups. Outcomes associated with additional outreach, beyond universal outreach, are not well known. Objective: To compare CRC screening completion by race and ethnicity, age, and sex after universal automated outreach and additional personalized outreach. Design, Setting, and Participants: This observational cohort study included screening-eligible individuals aged 50 to 75 years assessed during 2019 in a community-based organized CRC screening program within the Kaiser Permanente Northern California (KPNC) integrated health care delivery setting. For KPNC members who are not up to date with screening by colonoscopy, each year the program first uses automated outreach (mailed prescreening notification postcards and fecal immunochemical test [FIT] kits, automated telephone calls, and postcard reminders), followed by personalized components for nonresponders (telephone calls, electronic messaging, and screening offers during office visits). Data analyses were performed between November 2021 and February 2023 and completed on February 5, 2023. Exposures: Completed CRC screening via colonoscopy, sigmoidoscopy, or FIT. Main Outcomes and Measures: The primary outcome was the proportion of participants completing an FIT or colonoscopy after each component of the screening process. Differences across subgroups were assessed using the χ2 test. Results: This study included 1 046 745 KPNC members. Their mean (SD) age was 61.1 (6.9) years, and more than half (53.2%) were women. A total of 0.4% of members were American Indian or Alaska Native, 18.5% were Asian, 7.2% were Black, 16.2% were Hispanic, 0.8% were Native Hawaiian or Other Pacific Islander, and 56.5% were White. Automated outreach significantly increased screening participation by 31.1%, 38.1%, 29.5%, 31.9%, 31.8%, and 34.5% among these groups, respectively; follow-up personalized outreach further significantly increased participation by absolute additional increases of 12.5%, 12.4%, 13.3%, 14.4%, 14.7%, and 11.2%, respectively (all differences P < .05 compared with White members). Overall screening coverage at the end of the yearly program differed significantly among members who were American Indian or Alaska Native (74.1%), Asian (83.5%), Black (77.7%), Hispanic (76.4%), or Native Hawaiian or Other Pacific Islander (74.4%) compared with White members (82.2%) (all differences P < .05 compared with White members). Screening completion was similar by sex; older members were substantially more likely to be up to date with CRC screening both before and at the end of the screening process. Conclusions and Relevance: In this cohort study of a CRC screening program, sequential automated and personalized strategies each contributed to substantial increases in screening completion in all demographic groups. These findings suggest that such programs may potentially reduce differences in CRC screening completion across demographic groups.


Asunto(s)
Neoplasias Colorrectales , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , Persona de Mediana Edad , Anciano , Grupos Raciales , Etnicidad
13.
Clin. transl. oncol. (Print) ; 26(4): 864-871, Abr. 2024. tab
Artículo en Inglés | IBECS | ID: ibc-VR-49

RESUMEN

Purpose: Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers.Methods: Multicenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages. Results: Three hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy. Conclusion: Our study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved.(AU)


Asunto(s)
Humanos , Masculino , Femenino , Metástasis de la Neoplasia , Inestabilidad de Microsatélites , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Estudios Retrospectivos
14.
Clin. transl. oncol. (Print) ; 26(4): 891-904, Abr. 2024. ilus
Artículo en Inglés | IBECS | ID: ibc-VR-52

RESUMEN

Background: Recently, enhancer RNAs (eRNAs) have garnered attention as pivotal biomarkers for the onset and progression of cancer. However, the landscape of eRNAs and the implications of eRNA-based molecular subtypes in stage II/III colorectal cancer (CRC) remain largely unexplored. Methods: Comprehensive profiling of eRNAs was conducted on a public stage II/III CRC cohort with total RNA-seq data. We used unsupervised clustering of prognostic eRNAs to establish an eRNA-based subtyping system. Further evaluations included molecular characteristics, immune infiltration, clinical outcomes, and drug responses. Finally, we validated the eRNA-based subtyping system in The Cancer Genome Atlas (TCGA) CRC cohort. Results: We identified a total of 6453 expressed eRNAs, among which 237 were prognostic. A global upregulation of eRNAs was observed in microsatellite-stable (MSS) CRCs when compared to microsatellite instability-high (MSI-H) CRCs. Through consensus clustering, two novel molecular subtypes, termed Cluster 1(C1) and Cluster 2(C2), were further identified. C1, associated with the activation of epithelial–mesenchymal transition (EMT), hypoxia, and KRAS signaling pathways, showed poorer prognosis. C2, correlated with the canonical CRC subtype, exhibited superior survival outcomes. In addition, C1 showed enrichment with immune infiltration and more sensitivity to immune checkpoint inhibitors. Conclusion: Our study unravels the molecular heterogeneity of stage II/III CRC at the eRNA level and highlights the potential applications of the novel eRNA-based subtyping system in predicting prognosis and guiding immunotherapy.(AU)


Asunto(s)
Humanos , Masculino , Femenino , Inmunoterapia , Pronóstico , Heterogeneidad Genética , Inestabilidad de Microsatélites , Neoplasias Colorrectales/terapia
15.
Clin. transl. oncol. (Print) ; 26(4): 1012-1021, Abr. 2024. graf
Artículo en Inglés | IBECS | ID: ibc-VR-64

RESUMEN

Purpose: This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). Methods: We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan–Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. Results: The median follow‐up was 35.8 months (range 2.8–71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. Conclusions: For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.(AU)


Asunto(s)
Humanos , Terapia Neoadyuvante , Pronóstico , Estadificación de Neoplasias , Resultado del Tratamiento , Neoplasias Colorrectales , Estudios Retrospectivos
16.
Nanoscale ; 16(16): 7976-7987, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38567463

RESUMEN

Collective functionalization of the phytochemicals of medicinal herbs on nanoparticles is emerging as a potential cancer therapeutic strategy. This study presents the facile synthesis of surface-functionalized gold nanoparticles using Bacopa monnieri (Brahmi; Bm) phytochemicals and their therapeutically relevant mechanism of action in the colorectal cancer cell line, HT29. The nanoparticles were characterized using UV-visible spectroscopy, TEM-EDAX, zeta potential analysis, TGA, FTIR and 1H NMR spectroscopy, and HR-LC-MS. The particles (Bm-GNPs) were of polygonal shape and were stable against aggregation. They entered the target cells and inhibited the viability and clonogenicity of the cells with eight times more antiproliferative efficacy (25 ± 1.5 µg mL-1) than Bm extract (Bm-EX). In vitro studies revealed that Bm-GNPs bind tubulin (a protein crucial in cell division and a target of anticancer drugs) and disrupt its helical structure without grossly altering its tertiary conformation. Like other antitubulin agents, Bm-GNPs induced G2/M arrest and ultimately killed the cells, as confirmed using flow cytometry analyses. ZVAD-FMK-mediated global pan-caspase inhibition and the apparent absence of cleaved caspase-3 in treated cells indicated that the death did not involve the classic apoptosis pathway. Cellular ultrastructure analyses, western immunoblots, and in situ immunofluorescence visualization of cellular microtubules revealed microtubule-acetylation-independent induction of autophagy as the facilitator of cell death. Together, the data indicate strong antiproliferative efficacy and a possible mechanism of action for these designer nanoparticles. Bm-GNPs, therefore, merit further investigations, including preclinical evaluations, for their therapeutic potential as inducers of non-apoptotic cell death.


Asunto(s)
Autofagia , Neoplasias Colorrectales , Oro , Nanopartículas del Metal , Humanos , Oro/química , Oro/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Nanopartículas del Metal/química , Autofagia/efectos de los fármacos , Acetilación , Microtúbulos/metabolismo , Microtúbulos/efectos de los fármacos , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/tratamiento farmacológico , Células HT29 , Caspasas/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química
17.
Carbohydr Polym ; 335: 122010, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38616103

RESUMEN

The mesocarp (albedo) of passion fruit is considered a waste product but rich in soluble fibers, especially pectins. Biological activity and health benefits of pectins have recently emerged, especially in colorectal cancer and attenuating inflammation. Pectin conventional extraction often uses mineral acids, which can be hazardous to the environment, and alternatives can be costly. Here, we assessed a high-temperature and pressure method to extract pectin from the passion fruit albedo and evaluated the differences from the water-soluble fractions extracted. HPSEC, HPAEC, FTIR-ATR, and HSQC-NMR were performed to identify and confirm the highly methylated homogalacturonan structures. The heat-modified samples showed a decreased molecular size compared to the untreated sample. Colorectal cancer cell lines showed reduced viability after being treated with different doses of modified samples, with two of them, LW-MP3 and 4, showing the most potent effects. All samples were detected inside cells by immunofluorescence assay. It was observed that LW-MP3 and 4 upregulated the p53 protein, indicating cell-cycle arrest and the cleaved caspase-9 in one of the cell lines, with LW-MP4 enhancing cell death by apoptosis. Since the modified samples were composed of hydrolyzed homogalacturonans, those probably were the responsible structures for these anti-cancer effects.


Asunto(s)
Neoplasias Colorrectales , Passiflora , Frutas , Temperatura , Polisacáridos/farmacología , Pectinas/farmacología
18.
Mol Nutr Food Res ; 68(8): e2300820, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38600874

RESUMEN

Garlic is rich in bioactive compounds that are effective against colon cancer cells. This study tests the antioxidant and antiproliferative effects of cold-extracted white and black garlic extracts. Black garlic extracted in water (SSU) exhibits the highest antioxidant activity, phenolic content, and flavonoid content, while black garlic extracted in ethanol (SET) shows the lowest values. Caspase-3 activity is notably higher in the white garlic extracted in methanol (BME), white garlic extracted in methanol combines with 5-FU, black garlic extracted in ethanol (SET), black garlic extracted in ethanol combines with 5-fluorouracil (5-FU), and 5-FU treatments compare to the control group (p > 0.05). BME+5-FU displays the highest caspase-8 activity (p < 0.05). A decrease in NF-κB levels is observed in the SET+5-FU group (p>0.05), while COX-2 activities decrease in the BME, SET+5-FU, SET, and 5-FU groups (p>0.05). Wound healing increases in the BME, BME+5-FU, SET+5-FU, and 5-FU groups (p < 0.05). In conclusion, aqueous black garlic extract may exhibit pro-oxidant activity despite its high antioxidant capacity. It is worth noting that exposure to heat-treated food and increased sugar content may lead to heightened inflammation and adverse health effects. This study is the first to combine garlic with chemo-preventive drugs like 5-FU in Caco-2 cells.


Asunto(s)
Antioxidantes , Proliferación Celular , Fluorouracilo , Ajo , Extractos Vegetales , Humanos , Ajo/química , Extractos Vegetales/farmacología , Fluorouracilo/farmacología , Proliferación Celular/efectos de los fármacos , Células CACO-2 , Antioxidantes/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , FN-kappa B/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Fenoles/farmacología , Fenoles/análisis , Ciclooxigenasa 2/metabolismo , Caspasa 3/metabolismo , Flavonoides/farmacología , Flavonoides/análisis
19.
Nutrients ; 16(7)2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38613029

RESUMEN

Methionine dependence is a characteristic of most cancer cells where they are unable to proliferate when the essential amino acid methionine is replaced with its precursor homocysteine in the growing media. Normal cells, on the other hand, thrive under these conditions and are referred to as methionine-independent. The reaction that adds a methyl group from 5-methyltetrahydrofolate to homocysteine to regenerate methionine is catalyzed by the enzyme methionine synthase with the cofactor cobalamin (vitamin B12). However, decades of research have shown that methionine dependence in cancer is not due to a defect in the activity of methionine synthase. Cobalamin metabolism has been tied to the dependent phenotype in rare cell lines. We have identified a human colorectal cancer cell line in which the cells regain the ability to proliferation in methionine-free, L-homocystine-supplemented media when cyanocobalamin is supplemented at a level of 1 µg/mL. In human SW48 cells, methionine replacement with L-homocystine does not induce any measurable increase in apoptosis or reactive oxygen species production in this cell line. Rather, proliferation is halted, then restored in the presence of cyanocobalamin. Our data show that supplementation with cyanocobalamin prevents the activation of the integrated stress response (ISR) in methionine-deprived media in this cell line. The ISR-associated cell cycle arrest, characteristic of methionine-dependence in cancer, is also prevented, leading to the continuation of proliferation in methionine-deprived SW48 cells with cobalamin. Our results highlight differences between cancer cell lines in the response to cobalamin supplementation in the context of methionine dependence.


Asunto(s)
Neoplasias Colorrectales , Metionina , Humanos , Metionina/farmacología , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa , Vitamina B 12/farmacología , Homocistina , Racemetionina , Línea Celular , Homocisteína , Neoplasias Colorrectales/tratamiento farmacológico
20.
World J Surg Oncol ; 22(1): 99, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38627808

RESUMEN

BACKGROUND: Colorectal peritoneal metastases (CRPM) are present in 10-20% of patients at the time of their initial cancer diagnosis, and affects over 20% of those who develop colorectal cancer recurrence. Cytoreductive surgery (CRS) with HIPEC is firmly established as the optimal surgical treatment, but there is very little known about the benefit of repeat or iterative CRS. The aim of this review is to provide a systematic evaluation of the perioperative complications, survival outcomes and quality of life in patients undergoing repeat CRS with HIPEC for CRPM. METHODS: A systematic review of PubMed, Ovid MEDLINE, EMBASE, Scopus and Cochrane databases was performed to identify all studies that reported outcomes for repeat CRS with or without HIPEC for CRPM. RESULTS: Four hundred and ninety-three manuscripts were screened, and 15 retrospective studies were suitable for inclusion. Sample sizes ranged from 2 to 30 participants and comprised a total of 229 patients. HIPEC was used in all studies, but exact rates were not consistently stated. Perioperative morbidity was reported in four studies, between 16.7% and 37.5%. Nine studies reported mortality rate which was consistently 0%. The median overall survival after repeat CRS ranged from 20 to 62.6 months. No studies provided quality of life metrics. CONCLUSION: Repeat CRS for CRPM has perioperative morbidity and mortality rates comparable to initial CRS, and offers a potential survival benefit in selected patients. There is however limited high-quality data in the literature.


Asunto(s)
Neoplasias Colorrectales , Hipertermia Inducida , Neoplasias Peritoneales , Humanos , Neoplasias Peritoneales/secundario , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Colorrectales/patología , Procedimientos Quirúrgicos de Citorreducción , Estudios Retrospectivos , Calidad de Vida , Recurrencia Local de Neoplasia/patología , Terapia Combinada , Tasa de Supervivencia , Protocolos de Quimioterapia Combinada Antineoplásica
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