EphA2 gene targeting using neutral liposomal small interfering RNA (EPHARNA) delivery: A phase I clinical trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2604-TPS2604 ◽  
Author(s):  
Aung Naing ◽  
Gabriel Lopez-Berestein ◽  
Siqing Fu ◽  
Apostolia Maria Tsimberidou ◽  
Shubham Pant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Growth ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Constitutive Expression ◽  
Orthotopic Mouse Model ◽  
In Vivo Models ◽  
Independent Functions

TPS2604 Background: EphA2 is a member of the largest subfamily of receptor tyrosine kinases, with over 14 receptors and 8 ligands. EphA2 overexpression is common in many human cancers, including lung, breast, prostate, colorectal, pancreatic, melanoma, esophageal and endometrial cancers. EphA2 can function as an oncoprotein when introduced into cells with low expression. In addition, downregulation of constitutive expression reduces tumorigenicity in breast, endometrial, ovarian and pancreatic cancers in vitro and in vivo models. EphA2 is a desirable target because of its selective expression in cancer (vs. adult normal tissue), and its important role in promoting tumor growth and metastasis. It has kinase-dependent and independent functions, making it an ideal target for RNAi-based targeting. We have previously reported that EphA2 siRNA incorporated in DOPC nanoliposomes (EPHARNA) was highly effective in reducing EphA2 protein levels after a single dose. In addition, three weeks of treatment with EPHARNA (150 μg/kg twice weekly) in an orthotopic mouse model of ovarian cancer (HeyA8 or SKOV3ip1) significantly reduced tumor growth compared with non-silencing siRNA, and demonstrated synergistic anti-tumor activity when combined with conventional chemotherapy. EPHARNA underwent GLP development in 2 animal models (murine and primate) at M.D. Anderson to support the IND (#72924). The first-in-human trial (NCT01591356) is ongoing and recruiting study subjects. Methods: Adult Patients > 18 years of age with histologic proof of advanced recurrent solid tumors, who are not candidates for known regimens or protocol treatments of higher efficacy or priority. All patients (dose escalation and dose expansion phases) must be willing to undergo pre- and post-treatment biopsies. For dose expansion phase, patients must have EphA2 overexpression by IHC evaluation. Enrollment is ongoing for the dose escalation with the plan for dose expansion. A total of 16 patients have been enrolled and treated in the dose escalation phase. Clinical trial information: NCT01591356.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

CD30/CD16A Tandab AFM13-Induced Target Cell Lysis By NK-Cells Is Enhanced By CD137 Co-Stimulation and Blocking PD-1

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2747-2747 ◽  
Author(s):  
Xing Zhao ◽  
Narendiran Rajasekaran ◽  
Uwe Reusch ◽  
Jens-Peter Marschner ◽  
Martin Treder ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Target Cell ◽  
Tumor Size ◽  
Target Cells ◽  
In Vivo Models ◽  
Effector Cells ◽  
Cytotoxicity Assays

Abstract Introduction: AFM13 is a CD30/CD16A bispecific tetravalent TandAb antibody that recruits and activates NK-cells by specific binding to CD16A for targeted lysis of CD30+ tumor cells. Given promising clinical activity and safety profile of AFM13 and proof-of-mechanism demonstrating dependence on the immune response, potential synergy of AFM13 and checkpoint modulators was evaluated. Methods: Efficacy of AFM13 alone or in combination with anti-CTLA-4, anti-PD-1, or anti-CD137 antibodies was assessed by in vitro cytotoxicity assays with human PBMCs or enriched NK-cells and CD30+ target cells as well as patient-derived xenograft in vivo models with autologous PBMC. To evaluate NK-cell-mediated lysis of CD30+ lymphoma cell lines, 4 hour cytotoxicity assays were performed with PBMCs or enriched NK-cells as effector cells in the presence of suboptimal concentrations of AFM13 alone, and in combination with anti-CTLA-4, anti-PD-1, or anti-CD137 antibodies. For the in vivo model tumor fragments derived from surgical specimens of newly diagnosed patients with CD30+ Hodgkin Lymphoma were xenografted (PDX) in immuno-deficient mice. After 28 days mice were reconstituted with autologous patient-derived PBMC and treated with AFM13 alone and in combination with anti-CTLA-4, anti-PD-1, or anti-CD137 antibodies weekly for a total of three weeks. Tumor size, tumor-infiltrating human lymphocytes and intra-tumoral cytokines were evaluated on day 58. Results: AFM13 as a single agent at suboptimal concentrations induced effector-to-target cell-dependent lysis of CD30+ lymphoma cells up to 40% using enriched NK-cells as effector cells in a 4 hour in vitro assay. Immune-modulating antibodies alone mediated substantially lower lysis (<25%). However, the addition of anti-PD-1 or anti-CD137 to AFM13 strongly enhanced specific lysis up to 70%, whereas the addition of anti-CTLA-4 to AFM13 showed no beneficial effect. The most impressive increase of efficacy was observed when AFM13 was applied together with a combination of anti-PD-1 and anti-CD137. In vivo, reduction of tumor growth was observed when AFM13 and anti-PD-1 were used as single agents or when AFM13 was combined with anti-CD137. Synergy was most impressive in these PDX models for the combination of AFM13 and anti-PD-1 which led to a very strong reduction of tumor size. Of note, reduction of tumor growth was strongly correlated with infiltrating NK- and T-cells and intra-tumoral cytokines. Conclusions: The combination trials performed with companion intra-tumoral assessment of lymphocytes and cytokines may enhance the efficacy of AFM13 in patients. This may be explained by a potential cross-talk between NK-cells and T-cell which was enhanced when AFM13 was used in combination with checkpoint modulators. Disclosures No relevant conflicts of interest to declare.

scholarly journals Continuous endoglin (CD105) overexpression disrupts angiogenesis and facilitates tumor cell metastasis

Angiogenesis ◽  
2020 ◽  
Vol 23 (2) ◽  
pp. 231-247 ◽  
Author(s):  
Claudia Ollauri-Ibáñez ◽  
Elena Núñez-Gómez ◽  
Cristina Egido-Turrión ◽  
Laura Silva-Sousa ◽  
Elena Díaz-Rodríguez ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Subsequent Development ◽  
Cancer Prognosis ◽  
In Vivo Models ◽  
Mural Cells ◽  
Cell Metastasis ◽  
Tumor Cell Metastasis ◽  
Expression Characteristic

AbstractEndoglin (CD105) is an auxiliary receptor for members of the TFG-β superfamily. Whereas it has been demonstrated that the deficiency of endoglin leads to minor and defective angiogenesis, little is known about the effect of its increased expression, characteristic of several types of cancer. Angiogenesis is essential for tumor growth, so high levels of proangiogenic molecules, such as endoglin, are supposed to be related to greater tumor growth leading to a poor cancer prognosis. However, we demonstrate here that endoglin overexpression do not stimulate sprouting or vascularization in several in vitro and in vivo models. Instead, steady endoglin overexpression keep endothelial cells in an active phenotype that results in an impairment of the correct stabilization of the endothelium and the recruitment of mural cells. In a context of continuous enhanced angiogenesis, such as in tumors, endoglin overexpression gives rise to altered vessels with an incomplete mural coverage that permit the extravasation of blood. Moreover, these alterations allow the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.

scholarly journals Huzhangoside A Suppresses Tumor Growth through Inhibition of Pyruvate Dehydrogenase Kinase Activity

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 712 ◽  
Author(s):  
Choong-Hwan Kwak ◽  
Jung-Hee Lee ◽  
Eun-Yeong Kim ◽  
Chang Woo Han ◽  
Keuk-Jun Kim ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pyruvate Dehydrogenase ◽  
Malignant Tumors ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
In Vitro Assays ◽  
In Vivo Models

Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.

scholarly journals EPCO-11. IN VIVO FUNCTIONAL GENOMIC SCREEN IDENTIFIES WISP1 AS AN OVEREXPRESSED DRIVER OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii71-ii71
Author(s):  
Pushan Dasgupta ◽  
Joy Gumin ◽  
Piergiorgio Pettazzoni ◽  
Floris Barthel ◽  
Angela Deem ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Matrix Protein ◽  
Therapeutic Potential ◽  
Functional Characterization ◽  
Extracellular Matrix Protein ◽  
Functional Genomic ◽  
In Vivo Models ◽  
Genomic Screen

Abstract There is a tremendous need to identify new genetic drivers of glioblastoma which can serve as potential therapeutic targets. In order to find new drivers, we leveraged genomic datasets to conduct a context specific in vivo functional genomic screen of overexpressed and/or amplified genes in GBM. We identified WISP1, a secreted extracellular matrix protein, to be an overexpressed driver in GBM. Overexpression of WISP1 was able to drive tumor growth in various in vivo models. Knockdown of WISP1 with shRNAs resulted in reduced colony formation in vitro and reduced tumor growth in vivo. Rescue experiments validated that the shRNAs were on target. Functional characterization of the protein revealed that the TSP module is necessary for the phenotype. Intriguingly, overexpression of WISP1 lacking the signal peptide module for secretion resulted in a strong phenotype. Co-culture and conditioned medium experiments further supported a secretion independent intracellular role of WISP1 in GBM. Though WISP1 is a secreted protein we have found some basal localization in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target. This study has expanded our understanding of WISP1 by supporting a new role as a driver in GBM which can function in a non-canonical manner in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target.

The Hypoxia-Selective Epigenetic Agent, Rrx-001, Triggers Apoptosis and Overcomes Drug-Resistance in Multiple Myeloma Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 918-918
Author(s):  
Deepika Sharma Das ◽  
Arghya Ray ◽  
Yan Song ◽  
Paul Richardson ◽  
Bryan Oronsky ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Viability ◽  
Cancer Cell ◽  
Mechanism Of Action ◽  
Global Methylation ◽  
In Vivo Models

Abstract Introduction The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in multiple myeloma (MM) cells (Chauhan et al, Cancer Cell 2009, 16:309-323) BM hypoxia (low oxygenation) plays a role in promoting MM cell survival, drug resistance, migration, and metastasis. Novel therapies that selectively target the MM cell in its hypoxic BM milieu may therefore overcome conventional drug resistance. Recent studies led to the development of a novel aerospace industry-derived Phase 2 molecule RRx-001 with hypoxia-selective epigenetic and NO-donating properties. A Phase I clinical trial demonstrated promising evidence of anti-tumor activity in a heavily pretreated population with no dose-limiting toxicities (Reid et al. J Clin Oncol 32:5s, 2014 suppl; abstr 2578, Reid et al, Lancet Oncology, in press). RRx-001 is currently under investigation in multiple Phase II clinical trials. Here we examined both the mechanism of action and anti-MM activity of RRx-001 using in vitro and in vivo models of MM. Methods Cell viability, apoptosis, and migration assays were performed using MTT, Annexin V staining, and transwell Inserts, respectively. ROS and NO generation was measured as previously described (Chauhan et al., Blood, 2004, 104:2458). Synergistic anti-MM activity was assessed by isobologram analysisusing "CalcuSyn" software program. In vitro angiogenesis was assessed using matrigel capillary-like tube formation assays. DNMT1 activity was measured using DNMT1 assay kit. USP7 siRNA was purchased from Dharmacon. CB-17 SCID-mice were subcutaneously inoculated with MM.1S cells as previously described (Chauhan et al., Cancer Cell 2012, 11:345-358). Statistical significance of data was determined using a Student's t test. RRx-001 was obtained from EpicentRx, CA, USA; USP7 inhibitor P5091, bortezomib, SAHA, and pomalidomide were purchased from Selleck chemicals, USA. Results Treatment of MM cell lines (MM.1S, MM.1R, RPMI-8226, OPM2, H929, Dox-40 ARP-1, KMS-11, ANBL6.WT, ANBL6.BR, and LR5) and primary patient cells for 48h significantly decreased their viability (IC50 range 1.25nM to 2.5nM) (p < 0.05; n=3) without markedly affecting PBMCs from normal healthy donors, suggesting specific anti-MM activity and a favorable therapeutic index for RRx-001. Tumor cells from 3 of 5 patients were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. Moreover, RRx-001 inhibits proliferation of MM cells, even in the presence of BM stromal cells. Washout experiments showed that a short time (3h) exposure of MM cells to RRx-001 triggered irreversible cell death. RRx-001-triggered apoptosis is associated with: 1) induction of DNA damage response signaling via ATM/p53/gH2AX axis; 2) activation of caspases mediating both intrinsic and extrinsic apoptotic pathways; 3) increase in oxidative stress through release of ROS and generation of NO; and 4) decrease in DNMT1 activity and global methylation levels. Furthermore, RRx-001 blocked migration of MM cells and angiogenesis. Deubiqyitylating enzyme USP7 stimulates DNMT1 enzymatic activity. USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. Importantly, the combination of USP7 inhibitor P5091 and RRx-001 triggered synergistic anti-MM activity associated with a robust decrease in DNMT1 activity, as well as increased degradation of USP7 substrate MDM2 and induction of downstream p21/p53 signaling axis. In vivo studies using a subcutaneous human MM xenograft model shows that RRx-001 is well tolerated, inhibits tumor growth, and enhances survival. Finally, combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity in p53-WT and p53-null MM cells, and overcomes drug resistance. Conclusion Our preclinical studies demonstrate that RRx-001, a ROS-mediated epigenetic inhibitor with anti-angiogenic properties selectively targets MM cells in vivo and synergizes with existing anti-MM agents to overcome therapeutic resistance. Our data also suggest a potential mechanism of action for RRx-001-induced epigenetic changes via USP7-DNMT1 complex and downstream p53/p21 signaling cascade. Collectively, these results provide a rationale for rapid translation of RRx-001, either alone or in combination, in a clinical trial of relapsed refractory MM. Disclosures Oronsky: epicentrx: Employment. Scicinski:epicentrx: Employment. Chauhan:Stemline Therapeutics: Consultancy.

scholarly journals MCM2 and Carbonic Anhydrase 9 Are Novel Potential Targets for Neuroblastoma Pharmacological Treatment

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 471
Author(s):  
Patrizia Garbati ◽  
Raffaella Barbieri ◽  
Davide Cangelosi ◽  
Carlo Zanon ◽  
Delfina Costa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Carbonic Anhydrase ◽  
Tumor Growth ◽  
Cell Model ◽  
Tumor Growth Rate ◽  
In Vivo Models ◽  
Gene Sets ◽  
Carbonic Anhydrase 9

To overcome the lack of effective pharmacological treatments for high-risk neuroblastoma (HR-NB), the development of novel in vitro and in vivo models that better recapitulate the disease is required. Here, we used an in vitro multiclonal cell model encompassing NB cell differentiation stages, to identify potential novel pharmacological targets. This model allowed us to identify, by low-density RT-PCR arrays, two gene sets, one over-expressed during NB cell differentiation, and the other up-regulated in more malignant cells. Challenging two HR-NB gene expression datasets, we found that these two gene sets are related to high and low survival, respectively. Using mouse NB cisplatin-treated xenografts, we identified two genes within the list associated to the malignant stage (MCM2 and carbonic anhydrase 9), whose expression is positively correlated with tumor growth. Thus, we tested their pharmacological targeting as potential therapeutic strategy. We measured mice survival and tumor growth rate after xenografts of human NB treated with cisplatin in the presence of MCM2/carbonic anhydrase 9 inhibitors (ciprofloxacin and acetazolamide). MCM2 or carbonic anhydrase 9 inhibition significantly increased cisplatin activity, supporting their possible testing for NB therapy.

Halofuginone, a Novel Antimyeloma Agent, Upregulates C-Jun, JNK and P-53 Protein in Vitro, and Inhibits Tumor Growth and Improves Survival in in Vivo Multiple Myeloma(MM) Animal Models

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2754-2754
Author(s):  
Merav Leiba ◽  
Jana Jakubikova ◽  
Steffen Klippel ◽  
Constantine S. Mitsiades ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Oral Gavage ◽  
In Vivo Models ◽  
To Receive ◽  
P 53

Abstract Halofuginone, a synthetic derivative of quinazolinone alkaloid, previously has been shown to have anti-cancer effects in various solid and hematological malignancies. Halofuginone inhibits mainly collagen type I synthesis, and extracellular matrix formation, via the inhibition of TGFβ signaling, matrix metalloproteinase 2(MMP2), and angiogenesis. Last year, we first reported, that Halofuginone in a low doses (IC50 of 50—100 nM) induces cytotoxicity in multiple MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g. thalidomide and bortezomib) anti-MM agents and overcomes the survival and growth advantages conferred by interleukin-6, insulin-like growth factor-1 and by bone marrow stroma cells. Halofuginone induced apoptosis in a caspase 3, 8, and 9 dependent mechanisms, reduced mitochondrial membrane potential, and down regulated MCL1 protein. We now assessed the cytotoxic effect of Halofuginone in primary MM patient cells in vitro and, its effect on tumor growth and survival in in vivo models. We found that Halofuginone also induces growth inhibition and cell death in primary MM cells (n=4, IC50: 100–200nM). Importantly, Halofuginone demonstrated additive or synergistic effects with some of the established anti-MM agents such as Melphalan, Dexamethasone, and Lenalidomide. In addition, Halofuginone inhibits IL6 production in the supernatant of a co-culture of MM.1S cells with HS-5 stromal cell line. Mechanistically, Halofuginone induces MM cell death, which involves the up-regulation of c-jun NH2-terminal kinase signaling (JNK), c-Jun, as well as the p-53 proapoptotic protein. Additionally, the in vivo anti-MM activity of Halofuginone was evaluated in 2 separate in vivo models, a xenograft model in SCID mice (subcutaneous injection of MM1S cells), and a model of diffuse MM lesions in SCID-beige mice (generated by i.v. injections of OPM-2 cells). In both models, mice were first sublethally irradiated (200 rads), injected s.c or i.v., respectively, with 1×106 MM cells and then randomly assigned to receive, either treatment with 0.75mg/kg halofuginone (IP or by oral gavage, respectively; n=10) or vehicle only (n=10) on a cyclical schedule of 5 days-on/2 days-off. In both models, Halofuginone inhibited MM tumor growth and improved survival, 70% vs 40% at 140 days (NS) in the treated vs control group respectively (figure). Clinical evidence of adverse events (weight loss, vomiting) were not observed. Halofuginone may, thus represents a promising novel orally bioavailable anti-MM agent that needs further evaluation for possible clinical trials in MM. Diffuse MM lesions in SCID-beige mice. Animals were sub lethally irradiated (200rads), injected i.v. with 1×106 OPM2 cells and then randomly assigned to receive, either halofuginone treatment (by oral gavage; 0.75mg/kg (n=10) or vehicle only (n=10) on a cyclical schedule of 5 days-on/2 days-off. Figure Figure

scholarly journals Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Manfred Kunz ◽  
Madeleine Brandl ◽  
Animesh Bhattacharya ◽  
Lars Nobereit-Siegel ◽  
Alexander Ewe ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Prostate Carcinoma ◽  
Target Genes ◽  
Tumor Therapy ◽  
3D Models ◽  
Tumor Growth Inhibition ◽  
Melanoma Metastasis ◽  
In Vivo Models

Abstract Background MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibition of its translation. In cancer, several miRNAs are upregulated and play crucial roles in tumorigenesis, making the inhibition of these oncomiRs an interesting therapeutic approach. This can be achieved by directly complementary single-stranded anti-miRNA oligonucleotides (antimiRs). A major bottleneck in antimiR therapy, however, is their efficient delivery. The nanoparticle formation with polyethylenimine (PEI) may be particularly promising, based on the PEI’s ability to electrostatically interact with oligonucleotides. This leads to their protection and supports delivery. In the present study, we explore for the first time PEI for antimiR formulation and delivery. We use the branched low molecular weight PEI F25-LMW for the complexation of different antimiRs, and analyse tumor- and metastasis-inhibitory effects of PEI/antimiR complexes in different tumor models. Results In prostate carcinoma, transfection of antimiRs against miR-375 and miR-141 leads to tumor cell inhibition in 2D- and 3D-models. More importantly, an in vivo tumor therapy study in prostate carcinoma xenografts reveals anti-tumor effects of the PEI/antimiR complexes. In advanced melanoma and metastasis, we identify by a microRNA screen miR-150 as a particularly relevant oncomiR candidate, and validate this result in vitro and in vivo. Again, the systemic application of PEI/antimiR complexes inhibiting this miRNA, or the previously described antimiR-638, leads to profound tumor growth inhibition. These effects are associated with the upregulation of direct miRNA target genes. In a melanoma metastasis mouse model, anti-metastatic effects of PEI/antimiR treatment are observed as well. Conclusions We thus describe PEI-based complexes as efficient platform for antimiR therapy, as determined in two different tumor entities using in vivo models of tumor growth or metastasis. Our study also highlights the therapeutic relevance of miR-375, miR-141, miR-150 and miR-638 as target miRNAs for antimiR-mediated inhibition.

scholarly journals S‐allylcysteine inhibits tumor growth and progression of oral cancer in both in vitro and in vivo models

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Chiao-Ying Chang ◽  
Wei-Yao Huang ◽  
Shih-Yan Chen ◽  
Man-Hui Pai ◽  
Feng-Yao Tang
Keyword(s):  
Oral Cancer ◽  
Tumor Growth ◽  
In Vivo Models
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