Effect of Modified Sijunzi Decoction on Macrophage Polarization Into M1 Phenotype in a Balb/c Mouse Model of Breast Cancer

Abstract Background: The five-year survival rate of breast cancer is bleak because of the predilection for bone metastasis. Tumor-associated macrophages are involved in tumor metastasis and are divided into two antagonistic types, M1 and M2. This study aimed to detect the anti-tumor effect of the modified Sijunzi decoction (MSJZD) in a mouse model of breast cancer and explore whether MSJZD inhibited tumor metastasis by regulating macrophage polarization.Materials and methods: A luciferase-expressing mouse breast cancer cell line Luc-4T1 was inoculated into the right mammary fat pad of mice to establish a Balb/c mouse model of breast cancer. After inoculation for 24 h, the mice were randomly divided into the MSJZD group and control group (n = 5 per group). The mice in the MSJZD group were gavaged with 0.77 g/mL MSJZD once daily for 35 days, whereas those in the control group were administered the same volume of normal saline. Subsequently, the effects of MSJZD on tumor growth and macrophage polarization were investigated.Results: On day 35, MSJZD reduced tumor growth in the mouse model of breast cancer. Flow cytometry showed that the M1 marker (inducible nitric oxide synthase+) was increased in the MSJZD group relative to that in the control group, whereas the M2 marker (CD206+) did not exhibit significant differences between the two groups. The results indicated that MSJZD promoted macrophage polarization into the M1 phenotype.Conclusions: Our findings showed that MSJZD promoted macrophage polarization into the M1 phenotype, thus inhibiting tumor growth and metastasis in breast cancer.

Download Full-text

Astragalus Polysaccharide RAP Induces Macrophage Phenotype Polarization to M1 via the Notch Signaling Pathway

Molecules ◽

10.3390/molecules24102016 ◽

2019 ◽

Vol 24 (10) ◽

pp. 2016 ◽

Cited By ~ 6

Author(s):

Wei Wei ◽

Zhi-Peng Li ◽

Zhao-Xiang Bian ◽

Quan-Bin Han

Keyword(s):

Tumor Growth ◽

Notch Signaling ◽

Signaling Pathway ◽

Macrophage Polarization ◽

Notch Signaling Pathway ◽

Raw264.7 Cells ◽

Control Group ◽

Macrophage Phenotype ◽

Astragalus Polysaccharide ◽

M1 Phenotype

Macrophages occur in polarized phenotypes, whose characteristics determine the role they play in tumor growth. The M1 phenotype macrophages promote tumoricidal responses and suppress tumor growth. Our previous study showed that a polysaccharide isolated from Radix Astragali, named RAP, was itself non-cytotoxic but induced RAW264.7 cells’ cytotoxicity against cancer cells. The current study was undertaken to determine its mechanism. Series studies was conducted to show that RAP is able to induce much higher gene expression of M1 markers, including iNOS, IL-6, TNF-a, and CXCL10, compared with the control group. When RAP-induced BMDMs were transplanted together with 4T1 tumor cells in BALB/c mice, both tumor volume and tumor weight decreased. Further studies indicated that RAP induces the Notch signaling pathway in RAW264.7 cells. The function of Notch signaling in macrophage polarization was confirmed by using γ-secretase inhibitor. These results suggested that Astragalus polysaccharide RAP induces macrophage’s polarization to M1 phenotype via the Notch signaling pathway.

Download Full-text

Liposome formulations of combretastatin a4 and 4-arylcoumarin analog prodrugs: antitumor effect in the mouse model of breast cancer

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20125803326 ◽

2012 ◽

Vol 58 (3) ◽

pp. 326-338

Author(s):

E.V. Moiseeva ◽

N.R. Kuznetsova ◽

E.V. Svirshchevskaya ◽

N.V. Bovin ◽

N.S. Sitnikov ◽

...

Keyword(s):

Breast Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Antitumor Effect ◽

Sialyl Lewis X ◽

Antimitotic Agent ◽

Combretastatin A4 ◽

Mouse Breast Cancer

The antimitotic agent combretastatin A4 (СА-4) has been suggested as an antivascular agent for anticancer therapy relatively recently. To reduce systemic toxicity by means of administration in liposome formulations, in this study new lipophilic prodrugs, oleic derivatives of СА-4 and its 4-arylcoumarin analog (СА4-Ole and ArC-Ole, respectively), have been synthesized: Liposomes of 100 nm mean diameter prepared on the basis of egg phosphatidylcholine and phosphatidylinositol from bakers yeast have been shown to include completely up to 10 mol. % of СА4-Ole, or 7 mol. % of ArC-Ole. Also, prodrug bearing liposomes decorated with tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been constructed to achieve targeting to endothelium under neovascularization. The antitumor activity in vivo was studied in the model of slowly growing mouse breast cancer. Under the used dose (22 mg/kg) as well as the regimen of treatment (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal any anticancer effect, and oppositely even stimulated tumor growth. Liposome formulations of CA4-Ole did not show such stimulation. However, to achieve pronounced antitumor effect, number of injections of liposomes should be apparently elevated. New antimitotic agent ArC revealed cytotoxic activity of only one tenth value obtained for CA-4 in vitro in the culture of human breast carcinoma cells. Nevertheless, in vivo in the mouse model of breast cancer this compound showed antitumor effect under double СА-4 equivalent dose. The results demonstrate availability of SiaLeX-liposomes loaded with ArC-Ole: this preparation began to inhibit tumor growth already after the second injection. It is necessary further to choose doses and regimens of administration both for ArC and liposome formulations bearing ArC-Ole.

Download Full-text

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Integrative Cancer Therapies ◽

10.1177/1534735420949678 ◽

2020 ◽

Vol 19 ◽

pp. 153473542094967

Author(s):

Min Kyoon Kim ◽

Yesl Kim ◽

SeungHwa Park ◽

Eunju Kim ◽

Yerin Kim ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

High Fat Diet ◽

Tumor Volume ◽

Macrophage Polarization ◽

M2 Macrophage ◽

High Fat ◽

Low Intensity ◽

M2 Macrophage Polarization ◽

Low Intensity Exercise

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

Download Full-text

Thymoquinone Inhibits Tumor Growth and Induces Apoptosis in a Breast Cancer Xenograft Mouse Model: The Role of p38 MAPK and ROS

PLoS ONE ◽

10.1371/journal.pone.0075356 ◽

2013 ◽

Vol 8 (10) ◽

pp. e75356 ◽

Cited By ~ 90

Author(s):

Chern Chiuh Woo ◽

Annie Hsu ◽

Alan Prem Kumar ◽

Gautam Sethi ◽

Kwong Huat Benny Tan

Keyword(s):

Breast Cancer ◽

Mouse Model ◽

Tumor Growth ◽

P38 Mapk ◽

Xenograft Mouse Model ◽

Breast Cancer Xenograft

Download Full-text

Methylseleninic Acid Suppresses Breast Cancer Growth via the JAK2/STAT3 Pathway

Reproductive Sciences ◽

10.1177/1933719118815582 ◽

2018 ◽

Vol 26 (6) ◽

pp. 829-838 ◽

Cited By ~ 4

Author(s):

Changwei Qiu ◽

Tao Zhang ◽

Xinying Zhu ◽

Jinxia Qiu ◽

Kangfeng Jiang ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Western Blot ◽

Cancer Cell ◽

Anticancer Drug ◽

Cancer Cell Line ◽

Janus Kinase ◽

Cell Counting ◽

Stat3 Pathway ◽

Methylseleninic Acid

Previous studies show that methylseleninic acid (MSA), which is the most common selenium derivative used as a drug in humans, exerts specific cytotoxic effects in several cancer cell types. However, the complex mechanism of these effects has not been fully elucidated. Here, we demonstrate by Cell Counting Kit-8 in mouse breast cancer cell line 4T1 that MSA inhibits cell viability in a concentration-dependent (5, 10, 20 μmol/L) and time-dependent (6, 12, 24 hours) manner. Flow cytometry, Western blot, and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) analyses indicated that MSA inhibits cancer cell invasion and induces apoptosis by the activation of caspase-3, poly ADP ribose polymerase 1 (PARP1), and BCL2-associated X. Furthermore, MSA demonstrated anticancer activity by inhibiting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway. The MSA treatment for 24 hours decreased the phosphorylation of JAK2 and STAT3 in 4T1 cells by Western blot. We also confirmed this with the use of a JAK2 chemical inhibitor, AG490, as a positive control. In a 4T1 orthotopic allograft model, morphological and TdT-mediated dUTP nick-end labeling analyses showed that MSA treatment (1.5 mg/kg/weight) for 28 days inhibits tumor growth consistent with the clinical anticancer drug cyclophosphamide. Our observations demonstrate that MSA is a potent anticancer drug in breast cancer and uncovered a key role of the JAK2/STAT3 pathway in modulating tumor growth.

Download Full-text