Targeting of crosstalk between tumor and tumor microenvironment by β‐D mannuronic acid (M2000) in murine breast cancer model

Hosseini, Fatemeh Sadat; Hassannia, Hadi; Mahdian-shakib, Ahmad; Jadidi‐Niaragh, Farhad; Enderami, Seyed Ehsan; Fattahi, Mohammad Javad; Anissian, Ali; Mirshafiey, Abbas; Kokhaei, Parviz

doi:10.1002/cam4.1013

Cited by 41 publications

(26 citation statements)

References 50 publications

(58 reference statements)

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“…Therefore, M2000 is suggested to have therapeutic efficacy in RA via anti‐angiogenic mechanisms. Also, based on our previous study demonstrating the efficacy of M2000 in decreasing tumor growth and metastasis in murine breast cancer model, and regarding the central role of angiogenesis in the metastasis process, it is suggested that, in addition to preventing chronic inflammation, part of the efficacy of M2000 in that study is attributable to its anti‐angiogenic effects . The current study, together with our previous studies on M2000, clearly demonstrates the role of this molecule in modulating three distinct but related processes including inflammation, angiogenesis, and metastasis.…”

Section: Discussionsupporting

confidence: 71%

“…In an investigation, our findings showed that M2000 is able to decrease the activities of MMP‐2, MMP‐9 in 4T1 breast cancer cell line. Moreover, the in vivo results showed that M2000 strongly inhibits tumor growth and increases lifespan as compared with control mice . In another study, our results showed that M2000 is able to decrease the gene expression and gelatinolytic activities of MMP‐2 and MMP‐9 in PMA‐differentiated THP‐1 cell line likely through inhibiting CD147 .…”

Section: Discussionmentioning

confidence: 52%

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Anti‐angiogenesis effect of β‐D‐mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model

Rastegari-Pouyani

Mostafaie

Mansouri

et al. 2018

Clin Exp Pharma Physio

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Angiogenesis is a process through which new capillaries are formed from pre-existing ones, which contributes significantly to the pathogenesis of numerous diseases, such as cancer and chronic inflammatory disorders. The β-D-mannuronic acid (M2000) is a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive effects and is a matrix metalloproteinase (MMP) inhibitor. This research aimed to study the anti-angiogenesis effects of M2000 under in vitro and in vivo models. The cytotoxic and anti-proliferative effects of M2000 were examined using the trypan blue method and the MTT assay, respectively. The 3D collagen-cytodex model and the chick chorioallantoic membrane (CAM) assay were then used to evaluate the anti-angiogenesis property of M2000. Cytotoxicity assay revealed that M2000 (at concentrations of less than 100 μg/mL) had no cytotoxic effect on human umbilical vein endothelial cells (HUVECs). It was also illustrated that M2000 had little or no anti-proliferative effect on HUVECs. In addition, the anti-angiogenesis effects of M2000 were shown to be marginal in the in vitro model and both significant and dose-dependent in the in vivo status. This study showed that M2000 could be considered as an anti-angiogenic molecule which more likely exerts its activity mainly via indirect effects on endothelial cells and its anti-inflammatory effects may partly be attributable to its anti-angiogenic activity. Therefore, it could be recommended as a candidate for prevention and treatment of cancer, chronic inflammatory diseases, and other angiogenesis-related disorders.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 52%

Anti‐angiogenesis effect of β‐D‐mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model

Rastegari-Pouyani

Mostafaie

Mansouri

et al. 2018

Clin Exp Pharma Physio

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“…β-D mannuronic acid (BDM) is a MMP inhibitor, inhibiting MMP-2 and MMP-9 involved in invasion, metastasis, and angiogenesis 38 . BDM possesses anti-metastatic activity and inhibits tumor growth by suppressing inflammatory chemokine and tumor–promoting cytokines 39 . MMP-14 located on the cell surface, is a potential target to stop metastasis and a novel antibody-mediated MMP-14 blockade seems to limit hypoxia and metastasis in triple negative breast cancer (TNBC) models 40 .…”

Section: Introductionmentioning

confidence: 99%

Role of extracellular matrix in breast cancer development: a brief update

Jena

Janjanam²

2018

F1000Res

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Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and -14 play vital roles degrading the matrix proteins for cancer spread. The β-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components.

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“…In the study of BC murine model and 4T1 cell line by Mirshafiey and co‐workers, it has been shown that M2000 significantly decreases MMP‐2, MMP‐9 activities and adhesion of 4T1 cells to collagen I, fibronectin and laminin (major components of ECM) in a dose dependent manner . The M2000 strongly inhibits the tumour growth and increases lifespan in mice and decreases tumour mass size, which is associated with decrease in recruitment of inflammatory cells to tumour microenvironment and prevents tumour metastasis …”

Section: Discussionmentioning

confidence: 99%

“…In addition, M2000 is a reducer of C‐C Motif chemokine Ligand 22 (CCL22), transforming growth factor beta (TGFβ), Tregs and MDSCs. The aforementioned items play an important role in the progression of cancer . Based on these findings, the present study was designed to evaluate the efficacy of M2000 in the early stage of pre‐surgical BC patients under a randomize phase II clinical trial.…”

Section: Introductionmentioning

confidence: 99%

A randomized, controlled, phase II clinical trial of β‐D‐mannuronic acid (M2000) in pre‐surgical breast cancer patients at early stage (T1‐T2)

Kashefi

Omranipour

Mahmoodzadeh

et al. 2019

Clin Exp Pharma Physio

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Summary Following the potent efficacy of β‐D‐Mannuronic acid in a breast cancer murine model, we evaluated the efficacy of this novel non‐steroidal anti‐inflammatory drug in breast cancer patients in the present clinical trial. The study was an 8‐week randomized, controlled, phase II clinical trial (IRCT: 2017012213739N7 (in 48 pre‐surgical breast cancer patients. Patients who had breast cancer at early stage, with invasive ductal carcinoma, were placed on a waiting‐list for surgery and were allocated to the study. β‐D‐Mannuronic was administrated at a dose of two capsules (1000 mg/d) orally during a period of 8 weeks. The end point of this study was when the patients were admitted for surgery. Moreover, the patients' well‐being status was followed up on for safety. There were no statistically significant differences between treatment and non‐treatment groups at baseline. β‐D‐Mannuronic acid therapy, from 20 patients, showed that in one patient (5%) tumour size was decreased; in five patients (25%) tumour growth was stopped; and in 14 patients (70%) the growth rate in the treatment group did not show significant change, compared to the non‐treatment group. Evaluation of two tumour markers (carcinoembryonic antigen and cancer antigen 15‐3) showed that there was no significant difference between before and after treatment. Although the use of some non‐steroidal anti‐inflammatory drugs in a long time period has shown a prophylactic effect in breast cancer, their therapeutic efficacy in a short time period is unknown, whereas treatment with β‐D‐Mannuronic acid during 8 weeks could show 30% therapeutic effects in pre‐surgical breast cancer patients.

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Targeting of crosstalk between tumor and tumor microenvironment by β‐D mannuronic acid (M2000) in murine breast cancer model

Cited by 41 publications

References 50 publications

Anti‐angiogenesis effect of β‐D‐mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model

Anti‐angiogenesis effect of β‐D‐mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model

Role of extracellular matrix in breast cancer development: a brief update

A randomized, controlled, phase II clinical trial of β‐D‐mannuronic acid (M2000) in pre‐surgical breast cancer patients at early stage (T1‐T2)

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