scholarly journals Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models

2019 ◽  
Vol 20 (16) ◽  
pp. 3873 ◽  
Author(s):  
David Licha ◽  
Silvia Vidali ◽  
Sepideh Aminzadeh-Gohari ◽  
Oliver Alka ◽  
Leander Breitkreuz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Ketogenic Diet ◽  
Energy Supply ◽  
Control Diet ◽  
Tumor Xenograft ◽  
Tumor Growth Inhibition ◽  
Molecular Evidence ◽  
Fatty Acid Transport

The application of ketogenic diet (KD) (high fat/low carbohydrate/adequate protein) as an auxiliary cancer therapy is a field of growing attention. KD provides sufficient energy supply for healthy cells, while possibly impairing energy production in highly glycolytic tumor cells. Moreover, KD regulates insulin and tumor related growth factors (like insulin growth factor-1, IGF-1). In order to provide molecular evidence for the proposed additional inhibition of tumor growth when combining chemotherapy with KD, we applied untargeted quantitative metabolome analysis on a spontaneous breast cancer xenograft mouse model, using MDA-MB-468 cells. Healthy mice and mice bearing breast cancer xenografts and receiving cyclophosphamide chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of adjuvant KD in the context of tumor growth inhibition and suggest additional mechanisms of tumor suppression beyond the proposed constrain in energy supply of tumor cells.

scholarly journals Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models

2019 ◽  
Author(s):  
David Licha ◽  
Silvia Vidali ◽  
Sepideh Aminzadeh-Gohari ◽  
Oliver Alka ◽  
Leander Breitkreuz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Ketogenic Diet ◽  
High Performance ◽  
Control Diet ◽  
Tumor Xenograft ◽  
Tumor Growth Inhibition ◽  
Molecular Evidence ◽  
Fatty Acid Transport ◽  
Metabolome Analysis

Ketogenic diet (KD) is getting in the focus as auxiliary cancer therapy, since it provides sufficient energy supply for healthy cells, while impairing energy production in tumor cells underlying the Warburg effect. Thereby, it can assist in inhibiting tumor growth and simultaneously counteract cachexia, which is frequently observed in cancer patients under chemotherapy. In order to provide molecular evidence for the proposed synergistic inhibition of tumor growth, we applied untargeted quantitative metabolome analysis on a breast cancer xenograft mouse model. Healthy mice and such bearing breast cancer xenografts and receiving chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both, the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of KD in the context of tumor growth inhibition.

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. 

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1081-1081
Author(s):  
Ashley P Wright ◽  
Jodi D Bradley ◽  
Timothy Hagerty ◽  
Emily A Wyatt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Topoisomerase I Inhibitor ◽  
Polymeric Nanoparticle ◽  
Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

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 Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

2008 ◽  
Vol 11 (2) ◽  
Author(s):  
Alison J. Butt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Xenograft Model ◽  
Estrogen Receptor Α ◽  
Tumor Xenograft ◽  
Breast Cancers ◽  
Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

The effect of monotherapy and combined therapy with NSC-631570 (Ukrain) on growth of low- and high-metastasizing B16 melanoma in mice

2010 ◽  
Vol 17 (4) ◽  
pp. 339-349 ◽  
Author(s):  
LM Skivka ◽  
YaM Susak ◽  
OO Trompak ◽  
YuI Kudryavets ◽  
N Bezdeneznikh ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Combined Therapy ◽  
Tumor Growth Inhibition ◽  
Cell Cycle Distribution ◽  
Colorimetric Determination ◽  
Chelidonium Majus ◽  
Melanoma B16

Background. NSC-631570 (Ukrain) is a semisynthetic derivative of the Chelidonium majus alcaloids and the alkylans thiotepa. It exerts a selective cytotoxic effect on tumor cells in vitro and in vivo and shows the ability to modulate immunocyte functions. Purpose. The aim of our work was to carry out a comparative investigation of the effects of NSC-631570 alone or in combination with pathogen-associated molecules (PAM) on the growth of low- and high-metastasizing melanoma B16 in mice. Methods. NSC-631570 was administered intravenously and PAM intramuscularly to tumor-bearing mice seven times every third day, starting from the second day after the transplantation of tumor cells. The effect of monotherapy and combined therapy on tumor growth was evaluated by the indices of tumor growth inhibition in experimental animals. Cell cycle distribution of cancer cells was determined by flow cytometry. TAP1 and TAP2 expression was evaluated by RT-PCR. The metabolic activity of phagocytes was determined by NBT-test, phagocytosis was tested by flow cytometry, and arginase activity was estimated by colorimetric determination of urea. Results. Combined therapy and monotherapy with NSC-631570 resulted in significant inhibition of tumor growth in melanoma-bearing mice. Monotherapy with Ukrain was more effective in mice with high-metastasizing tumors. The therapeutic efficacy of NSC-631570 used in combination with PAM was more expressed in mice with low-metastasizing melanoma. Conclusion. The effectiveness of monotherapy and combined therapy with NSC-631570 in the treatment of melanoma B16 depends on the biological properties of the tumor and the immune state of the organism.

scholarly journals Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells

Oncotarget ◽  
2017 ◽  
Vol 8 (43) ◽  
pp. 73793-73809 ◽  
Author(s):  
Janja Završnik ◽  
Miha Butinar ◽  
Mojca Trstenjak Prebanda ◽  
Aleksander Krajnc ◽  
Robert Vidmar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cystatin C ◽  
Cancer Model ◽  
Breast Cancer Model

Heparanase Upregulates Synthesis and Expression of Syndecan-1 (CD138) - A Novel Growth Regulatory Loop for Myeloma Tumors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 625-625
Author(s):  
Yang Yang ◽  
Veronica MacLeod ◽  
Allison M. Theus ◽  
Ralph D. Sanderson ◽  
Fenghuang Zhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Surface ◽  
Tumor Growth ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Tumor Cells ◽  
Gene Array ◽  
Myeloma Cell ◽  
Myeloma Cell Line ◽  
Enhanced Expression

Abstract Syndecan-1 is a transmembrane heparan sulfate-bearing proteoglycan expressed on the surface of most myeloma tumor cells as well as some other tumors (e.g., breast cancer). The extracellular domain of syndecan-1 is shed from the surface of tumor cells by proteolytic enzymes and accumulates in the extracellular matrix and in the blood. High levels of soluble syndecan-1 in the blood are an indicator of poor prognosis for myeloma patients. Human heparanase-1 (heparanase) is an enzyme that releases biologically active fragments of heparan sulfate chains. In addition, growth factors within the tumor microenvironment that are bound to heparan sulfate are released by heparanase activity. In previous in vivo studies we demonstrated that enhanced expression of heparanase or soluble syndecan-1 by myeloma cells dramatically increases tumor growth and upregulates their spontaneous metastasis. We have now discovered that an increase in heparanase expression on tumor cells leads to enhanced expression, shedding and accumulation of syndecan-1 within the tumor microenvironment. One myeloma cell line and two breast cancer cell lines transfected with the cDNA for heparanase exhibit a dramatic increase in shed syndecan-1 as compared to equal number of control cells that were transfected with empty vector (2.7-fold, 6.3-fold and 17-fold increase over controls, respectively). This accumulation of syndecan-1 in the culture media was not accompanied by an increase in cell surface syndecan-1 levels as assessed by flow cytometry. Gene array analysis demonstrates that following transfection of the myeloma cell line with heparanase, the expression of the syndecan-1 gene is upregulated 1.4-fold. Together these findings suggest that expression of heparanase elevates syndecan-1 transcription and rate of shedding from the cell surface. To examine this further, ARH-77 cells, a B-lymphoblastoid cell line lacking significant expression of either syndecan-1 or heparanase, were transfected with the cDNA for heparanase. Following selection and confirmation that heparanase was stably expressed, the cells were analyzed by gene array and flow cytometry for syndecan-1 expression. Results show that expression of heparanase stimulates initiation of syndecan-1 transcription and expression on the cell surface. Karyotyping and analysis with a series of phenotypic markers for B cells show that the transfected ARH-77 cells maintain their general phenotype when syndecan-1 is upregulated by heparanase. Together these findings indicate that in addition to its role in cleaving heparan sulfate chains, the expression of heparanase upregulates the expression and shedding of syndecan-1 in tumor cells. Thus, the promotion by heparanase of tumor growth, angiogenesis and metastasis may, at least in part, be due to its positive effects on syndecan-1 expression and shedding which are also known to promote tumor progression in myeloma. Inhibitors of heparanase now being tested clinically may thus have the dual effect of blocking heparanase enzyme activity and decreasing syndecan-1 expression, both which could negatively affect tumor growth and metastasis.

scholarly journals Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model

Oncogene ◽  
2013 ◽  
Vol 33 (26) ◽  
pp. 3392-3400 ◽  
Author(s):  
M Butinar ◽  
M T Prebanda ◽  
J Rajković ◽  
B Jerič ◽  
V Stoka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cancer Model ◽  
Breast Cancer Model

Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Growth Inhibition ◽  
Human Breast ◽  
Akt Phosphorylation

Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report thecharacterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, andnonimmunogenic PMLA [poly(b-L-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemictreatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties werecovalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directedagainst HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab(Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptorantibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the hostendothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth ofHER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neureceptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopydemonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemictreatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth andtumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab orAON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLAnanoplatform for combination cancer therapy.

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