RESUMEN
BACKGROUND: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC. METHODS: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT. RESULTS: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses. CONCLUSIONS: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes.
RESUMEN
Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.
RESUMEN
The simultaneous increases in blood lactic acid and erythrocytes after intense exercise could suggest a link between lactate and the erythropoiesis. However, the effects of lactic acid on erythropoiesis remain to be elucidated. Here, we utilized a mouse model to determine the role of lactic acid in this process in parallel with studies using leukaemic K562 cells. Treatment of K562 cells in vitro with lactic acid increased the mRNA and protein expression of haemoglobin genes and the frequency of GPA+ cells. Also, increases in haematocrit and CD71-/Ter119+ erythroid cells were observed in lactic acid-treated mice, which showed a physiological increase in blood lactate. Mouse bone marrow CD34+/CD117- cells showed an increase in erythroid burst-forming units after stimulation with lactic acid in vitro. Furthermore, lactic acid increased the intracellular reactive oxygen species (ROS) content in bone marrow and in K562 cells. Erythroid differentiation induced in Haematopoietic Stem Cells (HSCs) and K562 cells by lactic acid was abolished by reducing ROS levels with SOD or 2-mercaptoethanol, which suggests that ROS is a critical regulator of this process. These findings provide a better understanding of the role of lactic acid in cellular metabolism and physiological functions.
Asunto(s)
Eritropoyesis/efectos de los fármacos , Ácido Láctico/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Precursoras Eritroides/efectos de los fármacos , Femenino , Expresión Génica , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Hemoglobinas/genética , Humanos , Células K562 , Ácido Láctico/metabolismo , Ratones Endogámicos BALB CRESUMEN
Aerobic glycolysis, a metabolic hallmark of cancer, is associated with radioresistance in non-small cell lung cancer (NSCLC). Pyruvate kinase M2 isoform (PKM2), a key regulator of glycolysis, is expressed exclusively in cancers. However, the impact of PKM2 silencing on the radiosensitivity of NSCLC has not been explored. Here, we show a plasmid of shRNA-PKM2 for expressing a short hairpin RNA targeting PKM2 (pshRNA-PKM2) and demonstrate that treatment with pshRNA-PKM2 effectively inhibits PKM2 expression in NSCLC cell lines and xenografts. Silencing of PKM2 expression enhanced ionizing radiation (IR)-induced apoptosis and autophagy in vitro and in vivo, accompanied by inhibiting AKT and PDK1 phosphorylation, but enhanced ERK and GSK3ß phosphorylation. These results demonstrated that knockdown of PKM2 expression enhances the radiosensitivity of NSCLC cell lines and xenografts as well as may aid in the design of new therapies for the treatment of NSCLC.
Asunto(s)
Apoptosis/efectos de la radiación , Autofagia/efectos de la radiación , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/radioterapia , Piruvato Quinasa/antagonistas & inhibidores , Tolerancia a Radiación/genética , Animales , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , ARN Interferente Pequeño/genética , Radiación Ionizante , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3(+) CD11c(+) dendritic cells (DCs) in human psoriatic lesions and in the skin of experimental preclinical K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesised, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the number and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.
Asunto(s)
Antígeno CD11c/inmunología , Células Dendríticas/inmunología , Psoriasis/inmunología , Tirosina Quinasa 3 Similar a fms/inmunología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Dermatitis/inmunología , Modelos Animales de Enfermedad , Humanos , Queratina-14/genética , Ratones Endogámicos BALB C , Ratones Transgénicos , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Psoriasis/tratamiento farmacológico , Tiadiazoles/farmacología , Tiadiazoles/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
Radiation therapy is a conventional strategy for treating advanced lung cancer yet is accompanied by serious side-effects. Its combination with other strategies, such as antiangiogenesis and gene therapy, has shown excellent prospects. As one of the potent endogenous vascular inhibitors, endostatin has been widely used in the antiangiogenic gene therapy of tumors. In the present study, LL/2 cells were infected with a recombinant adenovirus encoding endostatin (Ad-endostatin) to express endostatin. The results showed that LL/2 cells infected with the Ad-endostatin efficiently and longlastingly expressed endostatin. In order to further explore the role of Ad-endostatin combined with irradiation in the treatment of cancer, a murine lung cancer model was established and treated with Ad-endostatin combined with low-dose irradiation. The results showed that the combination treatment markedly inhibited tumor growth and metastasis, and prolonged the survival time of the tumor-bearing mice. Furthermore, this significant antitumor activity was associated with lower levels of microvessel density and anoxia factors in the Ad-Endo combined with irradiation group, and with an increased apoptotic index of tumor cells. In addition, no serious side-effects were noted in the combination group. Based on our findings, Ad-endostatin combined with low-dose irradiation may be a rational alternative treatment for lung cancer and other solid tumors.
Asunto(s)
Carcinoma Pulmonar de Lewis/terapia , Terapia Combinada/métodos , Endostatinas/metabolismo , Neoplasias Pulmonares/terapia , Animales , Carcinoma Pulmonar de Lewis/patología , Línea Celular , Terapia Combinada/efectos adversos , Dependovirus/genética , Endostatinas/genética , Terapia Genética , Vectores Genéticos/genética , Células HEK293 , Humanos , Neoplasias Pulmonares/patología , Ratones , Metástasis de la Neoplasia/terapia , Dosificación Radioterapéutica , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Combination of immunotherapy and chemotherapy has shown promise for cancer. Interleukin-7 (IL-7) can potentially enhance immune responses against tumor, while oxaliplatin (OXP), a platinum-based drug, can promote a favorable immune microenvironment and stimulate anticancer immune responses. We evaluated the anti-tumor activity of IL-7 combining OXP against a murine colon carcinoma in vitro and in vivo and studied the tumor immune microenvironment to investigate whether the combined treatment affects on the local immune cell populations. Utilizing lung and abdomen metastasis models by inoculation of CT26 mice colon cancer cells, we evaluated the anti-tumor efficacy of combining IL-7 and OXP in mice models. Tumor immune microenvironment was evaluated by flow cytometric analysis and immunohistochemical staining. Our study showed that the in vivo administration of IL-7 combined with OXP markedly inhibited the growth of tumors in lung and abdomen metastasis models of colon cancer. IL-7 alone had no effect on tumor growth in mice and IL-7 did not alter cell sensitivity to OXP in culture. The antitumor effect of combining IL-7 and OXP correlated with a marked increase in the number of tumor-infiltrating activated CD8+ T cells and a marked decrease in the number of regulatory T (Treg) cells in spleen. Our data suggest that OXP plus IL-7 treatment inhibits tumor cell growth by immunoregulation rather than direct cytotoxicity. Our findings justify further evaluation of combining IL-7 and chemotherapy as a novel experimental cancer therapy.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Inmunoterapia , Interleucina-7/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Antígenos CD8/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Femenino , Humanos , Inmunohistoquímica , Interleucina-7/farmacología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Compuestos Organoplatinos/farmacología , Oxaliplatino , Bazo/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunologíaRESUMEN
Human neutrophil peptides (HNPs) 1-3 possess a high degree of similarity and are deregulated in many types of human tumors. Previous studies have demonstrated that tumor cell lines and microdissected fresh tumor cells express HNP1-3. In vitro, HNP1-3 have been reported to be cytotoxic to various types of tumor cells. Previously, we observed that the intracellular expression of HNP1 increased plasma membrane permeability in A549 cells and inhibited in vivo tumor angiogenesis. Based on these findings, we inferred that the intratumoral expression of HNP1 may benefit chemotherapy in solid tumors. In the present study, we established a mouse 4T1 breast cancer model imitating locally advanced breast cancer (LABC) and we injected the mice intratumorally with plasmid HNP1 (pHNP1). Doxorubicin (Dox) was administered twice i.v. at 5 mg/kg body weight on day 1 and 8. The possible mechanisms were investigated by evaluating cell proliferation and apoptosis, intracellular Dox accumulation, mitochondrial transmembrane potential (ΔΨm) and ultrastructural alteration of intratumoral microvessels. Compared with the single agent treatment, the combination of Dox and pHNP1 resulted in a significant delay in in vivo tumor growth and a decrease in lung metastasis. This chemosensitization effect was also observed in an A549 lung cancer model treated with cisplatin (DDP) and pHNP1. MTT assay and Annexin V staining demonstrated that 4T1 cells pre-transfected with pHNP1 were significantly more sensitive to Dox, causing increased proliferation inhibition and apoptosis. Further investigations showed that the intracellular expression of HNP1 enhanced Dox accumulation and significantly impaired mitochondrial ΔΨm. Moreover, in tumor tissues, HNP1 mediated intratumoral microvessel normalization and caused significant in situ tumor cell apoptosis. Our study suggests that intratumoral expression of HNP1 can significantly improve the therapeutic efficacy of Dox in breast cancer, abrogate the influence of multidrug resistance and enhance medication safety. Our findings may be important for the clinical therapeutic strategies of cancer chemotherapy.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Neoplasias Pulmonares/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , Neovascularización Patológica/metabolismo , alfa-Defensinas/biosíntesis , Animales , Antibióticos Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Transporte Biológico , Línea Celular Tumoral , Cisplatino/farmacología , Terapia Combinada , Doxorrubicina/metabolismo , Resistencia a Antineoplásicos , Femenino , Expresión Génica , Humanos , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Potencial de la Membrana Mitocondrial , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Ensayos Antitumor por Modelo de Xenoinjerto , alfa-Defensinas/genéticaRESUMEN
Beta-defensins, small antimicrobial peptides, are involved in host immune responses to tumors. In this study, we used beta-defensin 2 (BD2) to explore the possible role of beta-defensins in cancer gene therapy. A recombinant plasmid expressing a secretable form of BD2 was constructed. The biological activities of BD2 in immature dendritic cells (iDCs) were tested in vitro and in vivo. The antitumor effects were investigated in three established tumor models. The secreted BD2 was detected and exhibited chemotactic activity in iDCs both in vitro and in vivo. Recruitment and activation of iDCs in tumor niches resulted in significant tumor growth inhibition. Adoptive transfer of splenocytes and depletion of immune cell subsets revealed that CD8(+) T lymphocyte responses mediated the increased tumor inhibition. Furthermore, we also found that chemotactic and maturation-inducing activities in iDCs in tumor milieu contributed to enhanced local antitumor effects. Our study indicates that gene therapy with BD2 can mediate specific antitumor immunity and augment local antitumor effects. Our study also suggested that beta-defensins may merit further exploration for cancer immunotherapy as promising immunogenes.
Asunto(s)
Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Neoplasias/genética , Neoplasias/inmunología , beta-Defensinas/genética , Animales , Línea Celular Tumoral , Factores Quimiotácticos/genética , Factores Quimiotácticos/inmunología , Quimiotaxis/genética , Quimiotaxis/inmunología , Células Dendríticas/patología , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Terapia Genética , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Ratones Noqueados , Neoplasias/terapia , Plásmidos/genética , Transfección , beta-Defensinas/inmunologíaRESUMEN
A de novo VEGFR2-inhibited compound SKLB1002 which is independently developed in our laboratory has been described for antiangiogenesis and displays a potent antitumor activity in vivo and in vitro. In the present investigation, we aim to prove that combination therapy of SKLB1002 with hyperthermia plays a synergy as an antitumor agent in solid tumor. In this study, we analyzed their synergetic inhibitory action on human umbilical vein endothelial cells (HUVEC), murine mammary cancer 4T1, murine colon carcinoma CT26 in vitro. Multiply-table tournament was performed to detect cell proliferation in vitro. 4T1 implantation and CT26 implantation in BALB/c mice were used to examine the activity of combination therapy of SKLB1002 with hyperthermia in vivo. Vascular density was determined by CD31 immunohistochemistry. TUNEL was used to measure apoptosis in tumor tissue. Metastasis assay was investigated via measurement of pulmonary metastasis nodules under the microscope. Potential toxicity of combination therapy was observed by histologic analysis of main organs stained with H&E. In vitro, the combination therapy significantly inhibited cell proliferation of HUVEC, 4T1 and CT26. In vivo, 4T1 and CT26 model experiments showed that combination therapy remarkably inhibited tumor growth and prolonged life span. When compared with controls, combination therapy reached 61 % inhibition index of tumor growth against CT26 and 51 % against 4T1. Moreover, it reduced angiogenesis and increased tumor apoptosis and necrosis. It was further found that combination therapy could efficiently prevent tumor from metastasizing to lung. Importantly, it had no toxicity to main organs including heart, liver, spleen, lung and kidney. Combination treatment has been proved to be a novel and strong strategy in clinical antitumor therapy. Our findings suggest that the combination therapy of SKLB1002 with hyperthermia has a synergistic antiangiogenesis, anticancer and promotion of apoptosis efficacy compared with controls. These findings could pave a new way in clinical tumor therapy.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Hipertermia Inducida/métodos , Quinazolinas/uso terapéutico , Tiadiazoles/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Animales , Antineoplásicos/efectos adversos , Apoptosis , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Neoplasias del Colon/patología , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Histocitoquímica , Hipertermia Inducida/efectos adversos , Inmunohistoquímica , Ratones Endogámicos BALB C , Necrosis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Quinazolinas/efectos adversos , Tiadiazoles/efectos adversos , Resultado del TratamientoRESUMEN
Ovarian cancers highly overexpress folate receptor α (FRα) and claudin3 (CLDN3), both of which are associated with tumor progression and poor prognosis of patients. Downregulation of FRα and CLDN3 in ovarian cancer may suppress tumor growth and promote benign differentiation of tumor. In this study, F-P-LP/CLDN3, a FRα targeted liposome loading with short hairpin RNA (shRNA) targeting CLDN3 was prepared and the pharmaceutical properties were characterized. Then, the antitumor effect of F-P-LP/CLDN3 was studied in an in vivo model of advanced ovarian cancer. Compared with Control, F-P-LP/CLDN3 promoted benign differentiation of tumor and achieved about 90% tumor growth inhibition. In the meantime, malignant ascites production was completely inhibited, and tumor nodule number and tumor weight were significantly reduced (p<0.001). FRα and CLDN3 were downregulated together in tumor tissues treated by F-P-LP/CLDN3. The antitumor mechanisms were achieved by promoting tumor cell apoptosis, inhibiting tumor cell proliferation and reducing microvessel density. Finally, safety evaluation indicated that F-P-LP/CLDN3 was a safe formulation in intraperitoneally administered cancer therapy. We come to a conclusion that F-P-LP/CLDN3 is a potential targeting formulation for ovarian cancer gene therapy.
Asunto(s)
Claudina-3/genética , Ácido Fólico/química , Neoplasias Ováricas/terapia , ARN Interferente Pequeño/administración & dosificación , Animales , Mama/metabolismo , Mama/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Terapia Genética , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , TransfecciónRESUMEN
Systemic administration of chemotherapy for cancer often has toxic side effects, limiting the doses that can be used in its treatment. In this study, we developed methoxy poly(ethylene glycol)-poly(caprolactone) (MPEG-PCL) micelles loaded with curcumin and doxorubicin (Cur-Dox/MPEG-PCL) that were tolerated by recipient mice and had enhanced antitumor effects and fewer side effects. It was shown that these Cur-Dox/MPEG-PCL micelles could release curcumin and doxorubicin slowly in vitro. The long circulation time of MPEG-PCL micelles and the slow rate of release of curcumin and doxorubicin in vivo may help to maintain plasma concentrations of active drug. We also demonstrated that Cur-Dox/MPEG-PCL had improved antitumor effects both in vivo and in vitro. The mechanism by which Cur-Dox/MPEG-PCL micelles inhibit lung cancer might involve increased apoptosis of tumor cells and inhibition of tumor angiogenesis. We found advantages using Cur-Dox/MPEG-PCL micelles in the treatment of cancer, with Cur-Dox/MPEG-PCL achieving better inhibition of LL/2 lung cancer growth in vivo and in vitro. Our study indicates that Cur-Dox/MPEG-PCL micelles may be an effective treatment strategy for cancer in the future.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/síntesis química , Neoplasias Pulmonares/tratamiento farmacológico , Nanocápsulas/administración & dosificación , Nanocápsulas/química , Poliésteres/química , Polietilenglicoles/química , Animales , Línea Celular Tumoral , Curcumina/administración & dosificación , Curcumina/química , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Femenino , Inyecciones Intravenosas , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Micelas , Nanocápsulas/ultraestructura , Tamaño de la Partícula , Resultado del TratamientoRESUMEN
An increasing number of studies support the use of metformin, a common antidiabetic drug, as a novel anticancer therapeutic. However, its mechanism of action has yet to be identified. In the current study, metformin was observed to effectively inhibit the growth of the K-ras mutant but not wild-type tumors in vivo. The antitumor effects of metformin were mediated by the induction of apoptosis and inhibition of proliferation in vivo. In addition, metformin induced apoptosis in the K-ras mutant tumors, A549 and PANC-1, but not in the K-ras wild-type tumor, A431, in vitro. Similarly, at lower concentrations, metformin inhibited cell proliferation in the K-ras mutant, but not in the K-ras wild-type tumor cells in vitro. These observations indicate that tumors with K-ras mutations are sensitive to metformin therapy. In addition, metformin significantly arrested K-ras mutant and wild-type tumor cells in G1 phase in vitro and metformin downregulated two important downstream effectors of the Ras signaling pathway in K-ras mutant tumors. Metformin was concluded to function as a potential K-ras-targeting agent that has potential for cancer therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Metformina/uso terapéutico , Proteínas ras/genética , Animales , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metformina/toxicidad , Ratones , Ratones Desnudos , Mutación , Transducción de Señal/efectos de los fármacos , Trasplante Heterólogo , Proteínas ras/metabolismoRESUMEN
Curcumin previously was proven to inhibit angiogenesis and display potent antitumor activity in vivo and in vitro. In the present study, we investigated whether a combination curcumin with hyperthermia would have a synergistic antitumor effect in the LL/2 model. The results indicated that combination therapy significantly inhibited cell proliferation of MS-1 and LL/2 in vitro. LL/2 experiment model also demonstrated that the combination therapy inhibited tumor growth and prolonged the life span in vivo. Furthermore, combination therapy reduced angiogenesis and increased tumor apoptosis. Our findings suggest that the combination therapy exerted synergistic antitumor effects, providing a new perspective fpr clinical tumor therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis , Carcinoma Pulmonar de Lewis/prevención & control , Curcumina/uso terapéutico , Hipertermia Inducida , Neovascularización Patológica/prevención & control , Animales , Western Blotting , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/patología , Proliferación Celular , Terapia Combinada , Femenino , Técnica del Anticuerpo Fluorescente , Liposomas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The use of adenoviral vector for gene therapy is still an important strategy for advanced cancers, however, the lack of the requisite coxsackie-adenovirus receptor in cancer cells and host immune response to adenovirus limit the application of adenoviral vector in vivo. METHOD: We designed the antiangiogenic gene therapy with recombinant PEDF adenovirus (Ad-PEDF) encapsulated in cationic liposome (Ad-PEDF/Liposome), and investigated the anti-tumor efficacy of Ad-PEDF/Liposome complex on inhibition of tumor metastasis. RESULTS: We found that systemic administration of Ad-PEDF/liposome was well tolerated and resulted in marked suppression of tumor growth, and was more potent than uncoated Ad-PEDF to induce apoptosis in B16-F10 melanoma cells and inhibit murine pulmonary metastases in vivo. After Ad-luciferase was encapsulated with liposome, its distribution decreased in liver and increased in lung. The anti-Ad IgG level of Ad-PEDF/Liposome was significantly lower than Ad-PEDF used alone. CONCLUSION: The present findings provide evidences of systematic administration of cationic liposome-encapsulated Ad-PEDF in pulmonary metastatic melanoma mice model, and show an encouraging therapeutic effect for further exploration and application of more complexes based on liposome-encapsulated adenovirus for more cancers.
Asunto(s)
Adenoviridae/genética , Proteínas del Ojo/genética , Terapia Genética/métodos , Liposomas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Melanoma/patología , Melanoma/terapia , Factores de Crecimiento Nervioso/genética , Serpinas/genética , Animales , Cationes , Femenino , Vectores Genéticos , Inmunoglobulina G/química , Liposomas/química , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Metástasis de la NeoplasiaRESUMEN
OBJECTIVE: To prepare water soluble curcumin liposome and investigate its anti-tumour and antiangiogenic effects. METHODS: Liposomal curcumin was prepared by alcohol injection method. Proliferation inhibition to murin Lewis lung cancer cell line LL/2 of curcumin liposome was evaluated by MTT assay. Apoptosis and cell cycle arrest induced by liposomal curcumin were analysed by flow cytometry. Anti-tumour effects were investigated in a murine lung cancer model, and the anti-angiogenic effect was determined by aginate encapsulation assay. RESULTS: In vitro, liposomal curcumin inhibits the proliferation of LL/2 cells and induces apoptosis and cell cycle arrest. In vivo, the systemic administration of liposomal curcumin resulted in the inhibition of tumour. Aginate encapsulation assay revealed angiogenesis was decreased by curcumin liposome. CONCLUSION: The curcumin liposome treatment can significantly inhibit tumour growth in vivo.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Curcumina/farmacología , Liposomas , Neoplasias Pulmonares/patología , Neovascularización Patológica/prevención & control , Animales , Apoptosis , Línea Celular Tumoral/efectos de los fármacos , RatonesRESUMEN
Thermotherapy and thermochemotherapy have been used in clinics to treat patients with malignant diseases, including colon cancer, and their efficacy has been well proved. Heat shock proteins (HSPs), especially Hsp70, play important roles in neutralizing their efficacy. It has been reported that quercetin can suppress cancer by inhibiting the intratumoral expression of Hsp70. This study was designed to investigate whether quercetin could enhance sensitivity to thermotherapy and thermochemotherapy. Soluble quercetin liposome was used in this study. The effects of quercetin were investigated in vitro and in mouse colon cancer models of subcutaneous tumor and peritoneal carcinomatosis. The results showed that quercetin liposome inhibited the upregulation of Hsp70 and enhanced apoptosis induced by hyperthermia and thermochemotherapy. Systemic administration of quercetin liposome can sensitize CT26 cells to thermotherapy and chemothermotherapy. This study suggests that quercetin liposome might be potentially applied for clinical cancer therapy.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/terapia , Hipertermia Inducida/métodos , Liposomas/farmacología , Quercetina/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Terapia Combinada , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Ratones , Ratones Endogámicos BALB C , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The objective of this study was to measure the antibody content of NuTu-19 ovarian cancer cells in serum samples using a quartz crystal microbalance (QCM) immunosensor. MATERIALS AND METHODS: NuTu-19 cells were first cultured onto the electrode surfaces of crystals in Dulbecco's modified Eagle medium, and then specified amounts of immunized serum samples of immunized rabbit were also added. The change in mass caused by specific adsorbtion of antibodies of NuTu-19 to the surfaces of the crystals was detected. RESULTS: The change in resonance frequency of crystals caused by immobilization of NuTu-19 cells was from 83 to 429 Hz. The antibody content of NuTu-19 detected was 341 ng/ul. The frequency shifts were linearly dependent on the amount of antibody mass in the range of 69 to 340 ng. The positive detection rate and the negative detection rate were 80% and 100%, respectively. CONCLUSION: This immunoassay provides a viable alternative to other early ovarian cancer detection methods and is particularly suited for health screening of the general population.
Asunto(s)
Anticuerpos/química , Sueros Inmunes/química , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/inmunología , Animales , Técnicas Biosensibles/métodos , Línea Celular Tumoral , Femenino , Inmunoensayo/métodos , Neoplasias Ováricas/sangre , Tecnicas de Microbalanza del Cristal de Cuarzo/métodos , Conejos , RatasRESUMEN
BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is associated with disruption of basement membranes of blood vessels and promotion of metastasis through the lymphatics. However, its prognostic value for survival in patients with gastric cancer remains controversial. METHOD: We therefore conducted a meta-analysis of the published literature in order to clarify the impact of MMP-9. Clinical studies were selected for further analysis if they provided an independent assessment of MMP-9 in gastric cancer and reported analysis of survival data according to MMP-9 expression. RESULTS: A total of 11 studies, covering 1700 patients, were included for meta- analysis. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive MMP-9 expression had an impact on overall survival: 1.25 (95% confidence interval 1.11-1.40) in all eligible studies; 1.13 (1.06-1.20) in 8 studies detecting MMP-9 by immunohistochemistry; 1.36 (1.12-1.65) in 7 studies from Asia. Only one study for DFS showed a significant impact on disease free survival (HR 1.73, 95%CI 1.27-2.34). CONCLUSIONS: Our findings suggested that MMP-9 protein expression might be a factor for a poor prognosis in patients with gastric cancer. However, the association was rather weak, so that more prospective studies should further explore the prognostic impact of MMP-9 mRNA and correlations between MMP-9 and clinicopathological characteristics.
Asunto(s)
Metaloproteinasa 9 de la Matriz/metabolismo , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/mortalidad , Biomarcadores de Tumor/metabolismo , Supervivencia sin Enfermedad , Humanos , Metástasis de la Neoplasia , Modelos de Riesgos ProporcionalesRESUMEN
INTRODUCTION: Many studies have reported that microRNA-21 (miR-21) mihght predict the survival outcome in non-small cell lung cancers (NSCLCs) but the opposite opinion has also been expressed. The aim of this study was to summarize the evidence for a prognostic role of miR-21. MATERIALS AND METHODS: All the eligible studies was searched by Medline and EMBASE and patients' clinical characteristics and survival outcome were extracted. Then a meta-analysis was performed to clarify the prognostic role of the miR-21 expression in different subgroups. RESULTS: A total of 8 eligible articles were yielded covering survival outcomes or clinical characteristics. The combined hazard ratio (HR) and 95% confidence interval (95% CI) for overall survival (OS) was 2.19 [0.76, 6.30], while the combined HR (95% CI) of Asian group for OS had a significant result, 5.49 [2.46, 12.27]. The combined HR (95% CI) for recurrence free survival or disease free survival (RFS/DFS) was 2.31 [1.52, 3.49]. Odds ratios (ORs) showed that the miR-21 expression was associated with lymph node status and histological type. CONCLUSION: miR-21 expression could predict the prognostic outcome of NSCLC in Asians, despite some deficiencies in the study data.