RESUMO
Studies have demonstrated that purported biofield therapy emitted from humans can inhibit the proliferation of cancer cells and suppress tumor growth in various cancers. We explored the effects of biofield therapy on tumor growth in the Lewis lung carcinoma and expanded mechanistic outcomes. We found biofield therapy did not inhibit tumor growth. However, the experimental (Ex) condition exposed tumors had a significantly higher percentage of necrosis (24.4 ± 6.8%) compared with that of the Control condition (6.5 ± 2.7%; P < .02) and cleaved caspase-3 positive cells were almost 2.3-fold higher (P < .05). Similarly, tumor-infiltrating lymphocytes profiling showed that CD8+/CD45+ immune cell population was significantly increased by 2.7-fold in Ex condition (P < .01) whereas the number of intratumoral FoxP3+/CD4+ (T-reg cells) was 30.4% lower than that of the Control group (P = .01), leading to a significant 3.1-fold increase in the ratio of CD8+/T-reg cells (P < .01). Additionally, there was a 51% lower level of strongly stained CD68+ cells (P < .01), 57.9% lower level of F4/80high/CD206+ (M2 macrophages; P < .02) and a significant 1.8-fold increase of the ratio of M1/M2 macrophages (P < .02). Furthermore, Ex exposure resulted in a 15% reduction of stem cell marker CD44 and a significant 33% reduction of SOX2 compared with that of the Controls (P < .02). The Ex group also engaged in almost 50% less movement throughout the session than the Controls. These findings suggest that exposure to purported biofields from a human is capable of enhancing cancer cell death, in part mediated through modification of the tumor microenvironment and stemness of tumor cells in mouse Lewis lung carcinoma model. Future research should focus on defining the optimal treatment duration, replication with different biofield therapists, and exploring the mechanisms of action.
Assuntos
Carcinoma , Neoplasias Pulmonares , Animais , Humanos , Pulmão , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral , Camundongos , Microambiente TumoralRESUMO
Biofield therapies have gained popularity and are being explored as possible treatments for cancer. In some cases, devices have been developed that mimic the electromagnetic fields that are emitted from people delivering biofield therapies. However, there is limited research examining if humans could potentially inhibit the proliferation of cancer cells and suppress tumor growth through modification of inflammation and the immune system. We found that human NSCLC A549 lung cancer cells exposed to Sean L. Harribance, a purported healer, showed reduced viability and downregulation of pAkt. We further observed that the experimental exposure slowed growth of mouse Lewis lung carcinoma evidenced by significantly smaller tumor volume in the experimental mice (274.3 ± 188.9 mm3) than that of control mice (740.5 ± 460.2 mm3; P < .05). Exposure to the experimental condition markedly reduced tumoral expression of pS6, a cytosolic marker of cell proliferation, by 45% compared with that of the control group. Results of reversed phase proteomic array suggested that the experimental exposure downregulated the PD-L1 expression in the tumor tissues. Similarly, the serum levels of cytokines, especially MCP-1, were significantly reduced in the experimental group ( P < .05). Furthermore, TILs profiling showed that CD8+/CD4- immune cell population was increased by almost 2-fold in the experimental condition whereas the number of intratumoral CD25+/CD4+ (T-reg cells) and CD68+ macrophages were 84% and 33%, respectively, lower than that of the control group. Together, these findings suggest that exposure to purported biofields from a human is capable of suppressing tumor growth, which might be in part mediated through modification of the tumor microenvironment, immune function, and anti-inflammatory activity in our mouse lung tumor model.
Assuntos
Carcinoma/patologia , Proliferação de Células/fisiologia , Neoplasias Pulmonares/patologia , Células A549 , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Citocinas/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/fisiologiaRESUMO
Purpose To assess for nanopore formation in bone marrow cells after irreversible electroporation (IRE) and to evaluate the antitumoral effect of IRE, used alone or in combination with doxorubicin (DOX)-loaded superparamagnetic iron oxide (SPIO) nanoparticles (SPIO-DOX), in a VX2 rabbit tibial tumor model. Materials and Methods All experiments were approved by the institutional animal care and use committee. Five porcine vertebral bodies in one pig underwent intervention (IRE electrode placement without ablation [n = 1], nanoparticle injection only [n = 1], and nanoparticle injection followed by IRE [n = 3]). The animal was euthanized and the vertebrae were harvested and evaluated with scanning electron microscopy. Twelve rabbit VX2 tibial tumors were treated, three with IRE, three with SPIO-DOX, and six with SPIO-DOX plus IRE; five rabbit VX2 tibial tumors were untreated (control group). Dynamic T2*-weighted 4.7-T magnetic resonance (MR) images were obtained 9 days after inoculation and 2 hours and 5 days after treatment. Antitumor effect was expressed as the tumor growth ratio at T2*-weighted MR imaging and percentage necrosis at histologic examination. Mixed-effects linear models were used to analyze the data. Results Scanning electron microscopy demonstrated nanopores in bone marrow cells only after IRE (P , .01). Average volume of total tumor before treatment (503.1 mm3 ± 204.6) was not significantly different from those after treatment (P = .7). SPIO-DOX was identified as a reduction in signal intensity within the tumor on T2*-weighted images for up to 5 days after treatment and was related to the presence of iron. Average tumor growth ratios were 103.0% ± 75.8 with control treatment, 154.3% ± 79.7 with SPIO-DOX, 77% ± 30.8 with IRE, and -38.5% ± 24.8 with a combination of SPIO-DOX and IRE (P = .02). The percentage residual viable tumor in bone was significantly less for combination therapy compared with control (P = .02), SPIO-DOX (P , .001), and IRE (P = .03) treatment. The percentage residual viable tumor in soft tissue was significantly less with IRE (P = .005) and SPIO-DOX plus IRE (P = .005) than with SPIO-DOX. Conclusion IRE can induce nanopore formation in bone marrow cells. Tibial VX2 tumors treated with a combination of SPIO-DOX and IRE demonstrate enhanced antitumor effect as compared with individual treatments alone. © RSNA, 2017 Online supplemental material is available for this article.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Eletroporação/métodos , Nanopartículas de Magnetita/química , Modelos Biológicos , Nanoporos , Animais , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Coelhos , Suínos , Tíbia/citologiaRESUMO
Introduction Oleandrin, a cardiac glycoside, exerts strong anti-proliferative activity against various human malignancies in in vitro cells. Here, we report the antitumor efficacy of PBI-05204, a supercritical C02 extract of Nerium oleander containing oleandrin, in a human pancreatic cancer Panc-1 orthotopic model. Results While all the control mice exhibited tumors by the end of treatment, only 2 of 8 mice (25%) treated for 6 weeks with PBI-05204 (40 mg/kg) showed dissectible tumor at the end of the treatment period. The average tumor weight (222.9 ± 116.9 mg) in mice treated with PBI-05204 (20 mg/kg) was significantly reduced from that in controls (920.0 ± 430.0 mg) (p < 0.05). Histopathologic examination of serial sections from each pancreas with no dissectible tumor in the PBI-05204 (40 mg/kg) treated group showed that the pancreatic tissues of 5/6 mice were normal while the remaining mouse had a tumor the largest diameter of which was less than 2.3 mm. In contrast, while gemcitabine alone did not significantly reduce tumor growth, PBI-05204 markedly enhanced the antitumor efficacy of gemcitabine in this particular model. Ki-67 staining was reduced in pancreatic tumors from mice treated with PBI-05204 (20 mg/kg) compared to that of control, suggesting that PBI-05204 inhibited the proliferation of the Panc-1 tumor cells. PBI-05204 suppressed expression of pAkt, pS6, and p4EPB1 in a concentration-dependent manner in both Panc-1 tumor tissues and human pancreatic cancer cell lines, implying that this novel botanical drug exerts its potent antitumor activity, at least in part, through down-regulation of PI3k/Akt and mTOR pathways.
Assuntos
Glicosídeos Cardíacos/farmacologia , Classe Ib de Fosfatidilinositol 3-Quinase/biossíntese , Nerium , Neoplasias Pancreáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Serina-Treonina Quinases TOR/biossíntese , Animais , Ciclo Celular , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Regulação para Baixo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-akt/biossíntese , GencitabinaRESUMO
UNLABELLED: Chronic hepatic diseases, such as cirrhosis, hepatocellular carcinoma, and virus-mediated immunopathogenic infections, affect billions of people worldwide. These diseases commonly initiate with fibrosis. Owing to the various side effects of antifibrotic therapy and the difficulty of diagnosing asymptomatic patients, suitable medication remains a major concern. To overcome this drawback, the use of cytokine-based sustained therapy might be a suitable alternative with minimal side effects. Here, we studied the therapeutic efficacy and potential mechanisms of interleukin (IL)-30 as antifibrosis therapy in murine liver fibrosis models. CCl4 or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) 0.1% (wt/wt) Purina 5015 Chow (LabDiet, St. Louis, MO) was fed for 3 weeks to induce liver fibrosis. Either control vector (pCtr) or pIL30 was injected hydrodynamically once per week. A significant decrease in collagen deposition and reduced expression of alpha-smooth muscle actin (α-SMA) protein indicated that IL-30-based gene therapy dramatically reduced bridging fibrosis that was induced by CCl4 or DDC. Immunophenotyping and knockout studies showed that IL-30 recruits natural-killer-like T (NKT) cells to the liver to remove activated hepatic stellate cells (HSCs) significantly and ameliorate liver fibrosis. Both flow cytometric and antibody-mediated neutralization studies showed that liver NKT cells up-regulate the natural killer group 2, member D (NKG2D) ligand and bind with the NKG2D ligand, retinoic acid early inducible 1 (Rae1), and positively activated HSCs to ameliorate liver fibrosis. Furthermore, adoptive transfer of liver NKT cells in T-cell-deficient mice showed reduction of fibrosis upon IL-30 administration. CONCLUSIONS: Highly target-specific liver NKT cells selectively remove activated HSCs through an NKG2D-Rae1 interaction to ameliorate liver fibrosis after IL-30 treatment.
Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Interleucinas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células T Matadoras Naturais/efeitos dos fármacos , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Animais , Tetracloreto de Carbono , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Estreladas do Fígado/metabolismo , Interleucinas/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/imunologia , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/metabolismo , PiridinasRESUMO
PURPOSE: To develop a clinically relevant porcine model of liver cirrhosis with portal hypertension by means of hepatic transarterial embolization. MATERIALS AND METHODS: Institutional animal care and use committee approval was obtained for all experiments. Pigs received transcatheter arterial infusion of a 3:1 mixture of iodized oil and ethanol into the hepatic artery in volumes of 16 mL in group 1 (n = 4), 28 mL in group 2 (n = 4), and 40 mL in group 3 (n = 4) with intent of bilobar distribution. Hepatic venous pressure gradient (HVPG) measurement, liver function tests, and volumetry were performed at baseline, at 2 weeks, and before necropsy. RESULTS: Cirrhosis was successfully induced in three animals that received 16 mL of the embolic mixture and in all four animals that received 28 mL. The animals in the 40-mL group did not recover from the procedure and were euthanized within 48 h. Increases in HVPG after 6-8 weeks versus baseline reached statistical significance (P < .05). Correlation between degree of fibrosis and volume of embolic agent did not reach statistical significance, but there was a trend toward increased fibrosis in the 28-mL group compared with the 16-mL group. CONCLUSIONS: Transcatheter hepatic arterial embolization can be used to create a reliable and reproducible porcine model of liver cirrhosis and portal hypertension.