scholarly journals Low dose amiodarone reduces tumor growth and angiogenesis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Eliana Steinberg ◽  
Arnon Fluksman ◽  
Chalom Zemmour ◽  
Katerina Tischenko ◽  
Adi Karsch-Bluman ◽  
...  
Keyword(s):  
Side Effects ◽  
Cancer Cells ◽  
Low Dose ◽  
Tumor Model ◽  
In Vitro Assays ◽  
Potential Candidate ◽  
Key Factor ◽  
Angiogenic Effect

Abstract Amiodarone is an anti-arrhythmic drug that was approved by the US Food and Drug Administration (FDA) in 1985. Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. However, it is also known to cause a variety of severe side effects. We hypothesized that in addition to the cytotoxic effects observed in cancer cells Amiodarone also has an indirect effect on angiogensis, a key factor in the tumor microenvironment. In this study, we examined Amiodarone's effects on a murine tumor model comprised of U-87 MG glioblastoma multiforme (GBM) cells, known to form highly vascularized tumors. We performed several in vitro assays using tumor and endothelial cells, along with in vivo assays utilizing three murine models. Low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect, suggesting dual cancer fighting properties. Our findings lay the ground for further research of Amiodarone as a possible clinical agent that, used in safe doses, maintains its dual properties while averting the drug’s harmful side effects.

scholarly journals Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

2020 ◽  
Author(s):  
Eliana Steinberg ◽  
Arnon Fluksman ◽  
Chalom Zemmour ◽  
Adi Karsch-Bluman ◽  
Yifat Brill-Karniely ◽  
...  
Keyword(s):  
Low Dose ◽  
Xenograft Model ◽  
In Vitro Assays ◽  
Potential Candidate ◽  
Angiogenic Activity ◽  
Anti Cancer ◽  
Angiogenic Effect ◽  
Cancer Activity

Abstract Background: Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. In this study, we examined Amiodarone's effects on glioblastoma multiforme (GBM), a highly aggressive and hypervascularized cancer. We hypothesized that Amiodarone would show an anti-angiogenic effect on GBM in addition to its previously suggested anti-cancer activity, and that an ultra-low dose would be both effective and possibly avert the drug’s side effects. Methods: The anti-cancer activity of Amiodarone was assessed by several in vitro assays using GBM cells. This included cytotoxicity, proliferation, transwell migration, Anoikis, colony-formation and three-dimensional (3D) spheroid growth assays. The anti-angiogenic effect of Amiodarone was tested on endothelial cells, using toxicity, proliferation, migration and tube formation in vitro assays. The anti-cancer and anti-angiogenic activity of Amiodarone was examined in vivo on three different murine models. C57BL/6J mice were utilized for the corneal neovascularization model and the Matrigel plug assay. Foxn1 nu mice were inoculated with GBM cells and used for the GBM tumor xenograft model.Results: In this study, we showed that Amiodarone has a significant anti-cancer and anti-angiogenic activity in vitro. Moreover, ultra-low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect in vivo. Conclusions: Our results strongly suggest that Amiodarone possess dual cancer fighting properties.

scholarly journals Apoptin Mediates Endogenous Mitophagy and Apoptosis by Regulating the Level of ROS in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Yiquan Li ◽  
Chao Shang ◽  
Zirui Liu ◽  
Jicheng Han ◽  
Wenjie Li ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Tumor Model ◽  
Activation Mechanism ◽  
Mouse Tumor ◽  
Liver Cancer Cells ◽  
Key Factor

Abstract Background: Apoptin, as a tumor-specific pro-apoptotic protein, apoptin plays an important role in the field of anti-tumor, but its autophagy activation mechanism and the interaction between autophagy and apoptosis have not been accurately elucidated. Here, we studied the mechanism of apoptosis and autophagy induced by apoptin and the interaction between autophagy and apoptosis. Methods: Through crystal violet staining and CCK-8 assay, we analyzed the effect of apoptin in inhibiting liver cancer in vitro, and also analyzed the effect of inhibiting liver cancer in vivo by establishing a nude mouse tumor model. Flow cytometry and fluorescence staining were used to analyze the main types of apoptosis and autophagy induced by apoptin. Subsequently, the relationship between apoptosis and autophagy induced by apoptin was analyzed. Then, flow cytometry was used to analyze the effect of ROS on apoptosis and autophagy mediated by apoptin. Then, the affect of ROS on apoptosis and autophagy mediated by apoptin was analyzed. Finally, the key genes leading to autophagy were analyzed by silencing different genes.Results: The results showed that apoptin can significantly increase the apoptosis and autophagy of liver cancer cells, and apoptin can cause mitophagy through the increase of NIX protein. Apoptin can also significantly reduce the level of cellular ROS, which is related to the autophagy and apoptosis of liver cancer cells caused by apoptin. The change of ROS may be a key factor causing apoptosis and autophagy. Conclusion: The above results indicate that the increase of ROS level after apoptin treatment of liver cancer cells leads to the loss of mitochondrial transmembrane potential, which leads to endogenous apoptosis and mitophagy while recruiting NIX. Therefore, ROS may be a key factor connecting endogenous apoptosis and mitophagy induced by apoptin in liver cancer cells.

Estrogen receptor β represses breast tumor growth and angiogenesis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10101-10101
Author(s):  
J. Hartman ◽  
K. Lindberg ◽  
J. Inzunza ◽  
J. Wan ◽  
A. Ström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Angiogenic Effect

10101 Background: Estrogens are well known stimulators of breast cancer cell growth in vitro as well as in vivo. Two different estrogen receptors exist, namely estrogen receptor (ER) α and β. ERα mediates the proliferative effect of estrogen in breast cancer cells and we have earlier shown that ERβ inhibits cell-cycle progression in vitro. Estrogens are well known stimulators of in vivo breast cancer cell growth as well as angiogenesis, and the effect is mediated through ERα. The function of ERβ in this context is not well understood. Methods: We have used ERα-positive T47D breast cancer cells stably transfected with a Tet/Off regulated ERβ expression vector system. The ERβ-inducible tumor cells are studied in vitro as well as in vivo. Results: By transplanting ERβ-inducible breast cancer cells into SCID-mice, we show that ERβ inhibits tumor growth and reduces the volume of established tumors. Furthermore, we show by immunohistochemistry, that the number of blood microvessels in the tumor periphery is decreased by ERβ expression, counteracting the well-known pro-angiogenic effect of ERα. By Western blot analysis on tumor extracts, we show that the concentration of the important pro-angiogenic growth factors VEGF and bFGF, normally expressed by breast tumor cells, is decreased in the ERβ-expressing tumors compared to the normal tumors. To exclude that the observed anti-angiogenic effect is just a result of reduced tumor growth, we incubated Tet/Off regulated ERβ expressing cells in vitro, during non-hypoxic conditions. We found that the expression of ERβ leads to decreased expression of VEGF and PDGFβ at the mRNA and protein-levels. In transient transfection assays, we found estrogen-ERα mediated up regulation of VEGF, PDGFβ and bFGF-promoter activities in T47D cells, and these activities were all suppressed following co-transfection with an ERβ-expression vector. Conclusions: We conclude that ERβ inhibits growth factor expression at transcriptional level in breast cancer cells; taken together, our data indicates that ERβ inhibits growth and angiogenesis of tumors formed by T47D breast cancer cells. This makes ERβ an interesting therapeutic target in breast cancer and perhaps treatment with the newly designed ERβ-selective ligands might work as a new anti-proliferative and anti-angiogenic therapy. No significant financial relationships to disclose.

3D-microdevice for the in vivo capture of cancer-associated circulating cells.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e579-e579
Author(s):  
Hélène Cayron ◽  
Alejandro Kayum Jiménez Zenteno ◽  
Aurore Esteve ◽  
Sylvain Sanson ◽  
Christophe Vieu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Expression Profiles ◽  
Antigen Expression ◽  
Sampling Bias ◽  
Additional Treatment ◽  
In Vitro Assays ◽  
Major Drawback ◽  
Direct Laser

e579 Background: Circulating tumor cells (CTCs) are cancer cells that have detached from a tumor and have entered into the blood circulation at a very low concentration (D. Shook, Mech. Dev., Nov 2003). CTCs have a strong prognostic value, as their number has been correlated to overall survival in different metastatic cancers (J. S. de Bono, Clin. Cancer Res., Oct 2008). Considering the rareness of CTCs in blood, capturing them in vitro is very challenging. CTCs being mainly larger and less deformable than most of blood cells, ISET was the first system exploiting their physical traits using a filtration membrane to enrich 10mL blood samples (G. Vona, Am. J. Pathol., Jan 2000). However, placing the trapping system directly within the bloodstream would increase the amount of blood screened and ensure no sampling bias. To our knowledge, the only system developed for in vivo capture of CTCs relies on an immunologic detection targeting CTCs with specific epithelial-cell adhesion molecules (N. Saucedo-Zeni, Int. J. Oncol., Oct 2012). The major drawback of this technique is the selection bias induced, given the strong heterogeneity of antigen expression profiles in CTC population as confirmed by several studies. Methods: Our device combines the advantages of in vivo capture and physical trapping of CTCs. A polymeric 3D net-like microdevice is fabricated using a Direct Laser Writing technique (Nanoscribe) and integrated onto a Nitinol guidewire to be introduced into the basilic vein through a routine 20G catheter. To optimize the design, we conducted simulation studies and in vitro assays using a fluidic platform reproducing in vivo conditions. Results: We succeeded in capturing PC3 human prostate cancer cells from 20 mL healthy donor blood spiked with 1,000 PC3 cells in 2 minutes, demonstrating the capability to capture CTCs in conditions close to those found in vivo, in terms of pressure and flow rate and without any additional treatment or dilution of the blood. Conclusions: This device could facilitate treatment personalization and follow-up. Its versatility should render it transposable to the capture of single or clustered CTCs, derived from all types of cancer and, by extension, to other circulating cellular and molecular biomarkers.

scholarly journals Anti-Tumoral and Anti-Angiogenic Effects of Low-Diluted Phenacetinum on Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Camille Fuselier ◽  
Sandrine Quemener ◽  
Eleonore Dufay ◽  
Camille Bour ◽  
Camille Boulagnon-Rombi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Side Effects ◽  
Ex Vivo ◽  
Tumor Model ◽  
Primary Cutaneous Melanoma ◽  
Relieve Pain ◽  
Melanoma Treatment ◽  
Vertical Growth Phase

Melanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly treated with a curative wide local excision, malignant melanoma has a poor prognosis and needs other therapeutic approaches. Angiogenesis is a normal physiological process essential in growth and development, but it also plays a crucial role in crossing from benign to advanced state in cancer. In melanoma progression, angiogenesis is widely involved during the vertical growth phase. Currently, no anti-angiogenic agents are efficient on their own, and combination of treatments will probably be the key to success. In the past, phenacetin was used as an analgesic to relieve pain, causing side effects at large dose and tumor-inducing in humans and animals. By contrast, Phenacetinum low-dilution is often used in skin febrile exanthema, patches profusely scattered on limbs, headache, or flushed face without side effects. Herein are described the in vitro, in vivo, and ex vivo anti-angiogenic and anti-tumoral potentials of Phenacetinum low-dilution in a B16F1 tumor model and endothelial cells. We demonstrate that low-diluted Phenacetinum inhibits in vivo tumor growth and tumor vascularization and thus increases the survival time of B16F1 melanoma induced-C57BL/6 mice. Moreover, Phenacetinum modulates the lung metastasis in a B16F10 induced model. Ex vivo and in vitro, we evidence that low-diluted Phenacetinum inhibits the migration and the recruitment of endothelial cells and leads to an imbalance in the pro-tumoral macrophages and to a structural malformation of the vascular network. All together these results demonstrate highly hopeful anti-tumoral, anti-metastatic, and anti-angiogenic effects of Phenacetinum low-dilution on melanoma. Continued studies are needed to preclinically validate Phenacetinum low-dilution as a complementary or therapeutic strategy for melanoma treatment.

scholarly journals MicroRNA-373-3p inhibits the growth of cervical cancer by targeting AKT1 both in vitro and in vivo

2021 ◽  
Author(s):  
Min-Min Yu ◽  
Gen-ju Wang ◽  
Kai-Hua Wu ◽  
Song-Lin Xue ◽  
Li- Li Ju ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Tumor Model ◽  
Cell Counting ◽  
Over Expression ◽  
Cervical Carcinoma Cell Line ◽  
Cervical Cancer Cells ◽  
Mrna And Protein Expression

Objective: In this study, we aimed to investigate the function of microRNA-373-3p (miR-373-3p) in the pathogenesis of cervical cancer. Methods: Human and mouse cervical cancer cell lines were transfected with miR-373-3p mimic and inhibitor. Cell proliferation and viability were evaluated with Cell Counting Kit-8 (CCK-8) assay and Lactate Dehydrogenase (LDH) assay, respectively. The AKT1-targeting role of miR-373-3p was analyzed by qPCR and Western blot. Finally, a mouse xenograft cervical tumor model was adopted to study the in vivo effect of miR-373-3p on tumor growth and the expression of AKT1. Results: Over-expression of miR-373-3p significantly reduced the proliferation of cervical carcinoma cell line in vitro. In addition, miR-373-3p overexpression also inhibited cervical cancer growth in tumor-bearing mice. Mechanistically, we found that AKT1 gene can be targeted by miR-373-3p. MiR-373-3p mimic decreased the mRNA and protein expression of AKT1, while the miR-373-3p inhibitor increased the level of AKT1 in cervical cancer cells. AKT1 overexpression rescued the proliferation of cervical cancer cells transfected with miR-373-3p. Conclusion: MiR-373-3p can serve as a novel anti-tumor microRNA in cervical cancer by targeting AKT1.

scholarly journals Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xi Zhang ◽  
Guoqing Hou ◽  
Andong Liu ◽  
Hui Xu ◽  
Yang Guan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Treatment Strategies ◽  
Ovarian Cancer Cells

Abstract Ovarian cancer remains the most lethal gynecologic malignancy with late detection and acquired chemoresistance. Advanced understanding of the pathophysiology and novel treatment strategies are urgently required. A growing body of proteomic investigations suggest that phosphorylation has a pivotal role in the regulation of ovarian cancer associated signaling pathways. Matrine has been extensively studied for its potent anti-tumor activities. However, its effect on ovarian cancer cells and underlying molecular mechanisms remain unclear. Herein we showed that matrine treatment inhibited the development and progression of ovarian cancer cells by regulating proliferation, apoptosis, autophagy, invasion and angiogenesis. Matrine treatment retarded the cancer associated signaling transduction by decreasing the phosphorylation levels of ERK1/2, MEK1/2, PI3K, Akt, mTOR, FAK, RhoA, VEGFR2, and Tie2 in vitro and in vivo. Moreover, matrine showed excellent antitumor effect on chemoresistant ovarian cancer cells. No obvious toxic side effects were observed in matrine-administrated mice. As the natural agent, matrine has the potential to be the targeting drug against ovarian cancer cells with the advantages of overcoming the chemotherapy resistance and decreasing the toxic side effects.

Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3837-3844 ◽  
Author(s):  
Farida Djouad ◽  
Pascale Plence ◽  
Claire Bony ◽  
Philippe Tropel ◽  
Florence Apparailly ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Side Effects ◽  
Tumor Growth ◽  
Tumor Model ◽  
Bone Morphogenetic Protein 2 ◽  
Melanoma Tumor ◽  
Immunocompetent Mice

Abstract Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on “activation” of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest. (Blood. 2003;102:3837-3844)

scholarly journals Selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12–IFN-γ

2017 ◽  
Vol 114 (43) ◽  
pp. 11482-11487 ◽  
Author(s):  
Madhuchhanda Kundu ◽  
Avik Roy ◽  
Kalipada Pahan
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Cancer ◽  
Critical Role ◽  
Tumor Model ◽  
Cell Mediated Immunity ◽  
Ifn Γ

Cancer cells are adept at evading cell death, but the underlying mechanisms are poorly understood. IL-12 plays a critical role in the early inflammatory response to infection and in the generation of T-helper type 1 cells, favoring cell-mediated immunity. IL-12 is composed of two different subunits, p40 and p35. This study underlines the importance of IL-12 p40 monomer (p40) in helping cancer cells to escape cell death. We found that different mouse and human cancer cells produced greater levels of p40 than p40 homodimer (p402), IL-12, or IL-23. Similarly, the serum level of p40 was much greater in patients with prostate cancer than in healthy control subjects. Selective neutralization of p40, but not p402, by mAb stimulated death in different cancer cells in vitro and in vivo in a tumor model. Interestingly, p40 was involved in the arrest of IL-12 receptor (IL-12R) IL-12Rβ1, but not IL-12Rβ2, in the membrane, and that p40 neutralization induced the internalization of IL-12Rβ1 via caveolin and caused cancer cell death via the IL-12–IFN-γ pathway. These studies identify a role of p40 monomer in helping cancer cells to escape cell death via suppression of IL-12Rβ1 internalization.

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