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. 

scholarly journals Breast Tumor Cells Highly Resistant to Drugs Are Controlled Only by the Immune Response Induced in an Immunocompetent Mouse Model

2019 ◽  
Vol 18 ◽  
pp. 153473541984804 ◽  
Author(s):  
Paola Lasso ◽  
Mónica Llano Murcia ◽  
Tito Alejandro Sandoval ◽  
Claudia Urueña ◽  
Alfonso Barreto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Tumor Cells ◽  
High Capacity ◽  
Cancer Cell Line ◽  
Tumor Model ◽  
Main Element ◽  
In Vivo Models

Background: The tumor cells responsible for metastasis are highly resistant to chemotherapy and have characteristics of stem cells, with a high capacity for self-regeneration and the use of detoxifying mechanisms that participate in drug resistance. In vivo models of highly resistant cells allow us to evaluate the real impact of the immune response in the control of cancer. Materials and Methods: A tumor population derived from the 4T1 breast cancer cell line that was stable in vitro and highly aggressive in vivo was obtained, characterized, and determined to exhibit cancer stem cell (CSC) phenotypes (CD44+, CD24+, ALDH+, Oct4+, Nanog+, Sox2+, and high self-renewal capacity). Orthotopic transplantation of these cells allowed us to evaluate their in vivo susceptibility to chemo and immune responses induced after vaccination. Results: The immune response induced after vaccination with tumor cells treated with doxorubicin decreased the formation of tumors and macrometastasis in this model, which allowed us to confirm the immune response relevance in the control of highly chemotherapy-resistant ALDH+ CSCs in an aggressive tumor model in immunocompetent animals. Conclusions: The antitumor immune response was the main element capable of controlling tumor progression as well as metastasis in a highly chemotherapy-resistant aggressive breast cancer model.

scholarly journals Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

2021 ◽  
Vol 22 (17) ◽  
pp. 9279
Author(s):  
Inés Martínez-Pena ◽  
Pablo Hurtado ◽  
Nuria Carmona-Ule ◽  
Carmen Abuín ◽  
Ana Belén Dávila-Ibáñez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Molecular Mechanisms ◽  
Zebrafish Embryo ◽  
Cancer Metastasis ◽  
Fluid Shear Stress ◽  
In Vivo Models

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

scholarly journals Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2204
Author(s):  
Meng-Die Yang ◽  
Yang Sun ◽  
Wen-Jun Zhou ◽  
Xiao-Zheng Xie ◽  
Qian-Mei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cell Viability ◽  
Synergistic Effects ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Tgf Β1

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

scholarly journals Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

2020 ◽  
Author(s):  
Patrycja Guzik ◽  
Klaudia Siwowska ◽  
Hsin-Yu Fang ◽  
Susan Cohrs ◽  
Peter Bernhardt ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Survival Time ◽  
Tumor Cells ◽  
Median Survival ◽  
Breast Tumor ◽  
Median Survival Time ◽  
Therapy Outcome ◽  
Minor Effect

Abstract Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

scholarly journals Mibefradil inhibits the proliferation of triple-negative breast cancer by targeting AURKA to regulate apoptosis signal pathway

2021 ◽  
Author(s):  
Xu Han ◽  
Xiujuan Qu ◽  
Beixing Liu ◽  
Yizhe Wang ◽  
Yang Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Molecular Docking ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Drug ◽  
Specific Gene ◽  
In Vivo Models

Abstract Background: Triple negative breast cancer (TNBC) is a tumor characterized by high recurrence and mortality, but without effective targeted therapy. It is urgent to explore new treatment strategy to improve the efficacy of TNBC therapy. Methods: Transcriptomic profiling datasets of TNBC were used for screening TNBC specific gene sets. Drug prediction was performed in Connectivity map (CMap) database. Molecular docking method was used for analyzing drug targets. In vitro and in vivo models of TNBC were constructed to examine the drug efficacy. Results: We screened out Mibefradil, a T-type Ca2+ channel blocker, might be a potential therapeutic drug for TNBC by transcriptomics and bioinformatics analysis, and verified that Mibefradil could inhibit the proliferation of TNBC cells by inducing apoptosis and cell cycle arrest. Furthermore, by network pharmacology and molecular docking analysis, AURKA was predicted as the most possible drug target of Mibefradil. Finally, it was proved that Mibefradil treatment could induce apoptosis by decreasing protein expression and phosphorylation level of AURKA in vitro and in vivo. Conclusions: Mibefradil played anti-cancer role in TNBC cells by targeting to AURKA to induce cell cycle and apoptosis. Our results repurposed Mibefradil as a potential targeted drug of TNBC and provided a fundamental research for a novel strategy TNBC treatment.

scholarly journals Association of CD44−/CD24− Breast Cancer Cells with Late Stage Tumor Recurrence

2020 ◽  
Author(s):  
Xinbo Qiao ◽  
Yixiao Zhang ◽  
Lisha Sun ◽  
Qingtian Ma ◽  
Jie Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Tumor Metastasis ◽  
Cancer Prognosis ◽  
Molecular Events ◽  
Cell Conversion ◽  
Tissue Specimens ◽  
Distant Tumor

AbstractTumor metastasis remains the main cause of breast cancer-related deaths, especially the later breast cancer distant metastasis. This study assessed CD44−/CD24− tumor cells in 576 tissue specimens for associations with clinicopathological features and metastasis and then investigated the underlying molecular events. The data showed that level of CD44−/CD24− cells was associated with later postoperative distant tumor metastasis. Furthermore, CD44−/CD24− triple negative cells could spontaneously convert into CD44+/CD24− cancer stem cells (CSCs) with properties similar to CD44+/CD24− CSCs from parental MDA-MB-231 cells in terms of gene expression, tumor cell xenograft formation, and lung metastasis in vitro and in vivo. Single-cell RNA sequencing identified RHBDL2 as a regulator that enhanced spontaneous CD44+/CD24− CSC conversion, whereas knockdown of RHBDL2 expression inhibited YAP/NF-κB signaling and blocked spontaneous CD44−/CD24− cell conversion to CSCs. These data suggested that the level of CD44−/CD24− tumor cells could predict breast cancer prognosis, metastasis, and response to adjuvant therapy.

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

scholarly journals TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 868
Author(s):  
Florian Drescher ◽  
Patricia Juárez ◽  
Danna L. Arellano ◽  
Nicolás Serafín-Higuera ◽  
Felipe Olvera-Rodriguez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Kinase Inhibitors ◽  
Disseminated Tumor Cells ◽  
Tyrosine Kinase Receptor ◽  
In Vivo Models ◽  
Hematopoietic Stem ◽  
Cell Dormancy

Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.

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