Biochemical and Biophysical Research Communications
β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer
Introduction
Lung cancer is the most common cancer worldwide. There were more than 1.8 million new cases (13% of total cancer incidence) and almost 1.6 million deaths (20% of total cancer mortality), as estimated in 2012 [1]. More than one third of new cases occurred in China [2].
Macrophages are important residents in solid tumor and they also referred to tumor-associated macrophages (TAMs). Macrophages are divided into two distinct phenotypes: the classically activated (M1) phenotype which is involved in the antitumor immunity; and the alternative activated (M2) phenotype which has pro-tumoral properties. Many studies have found that TAMs are mostly M2 polarized [3], [4], they are reported to promote tumor growth, survival, and may result in resistance to tumor therapies [5]. Infiltration of TAMs correlates with poor prognosis in most human tumors [6], [7], [8]. These suggest TAMs could be an attractive target for anti-cancer therapy.
β-elemene, the active component of elemene (1-methyl-1-vinyl-2, 4-diisopropenyl-cyclohexane, C15H24), is extracted from the Chinese medicine herb Curcuma Wenyujin. It has been proven to have anti-tumor activity in broad range of solid tumors [9], [10], [11]. β-elemene induced apoptosis and cell cycle arrest in non-small cell lung cancer (NSCLC) [12]. It also inhibited stemness and epithelial-to-mesenchymal transition related molecules expression in glioblastoma cells [13] or breast cancer cells [14], [15]. Studies showed that β-elemene impaired chemoresistance in NSCLC cells [16], glioblastoma cells [17], breast cancer cells [18] and ovarian cancer cells [19]. In China, β-elemene has been applied to clinical, and it presents fewer side effects than other cytotoxic agents. β-elemene is also confirmed as a radiosensitizer in recent years. It sensitized the lung cancer cells by enhancing DNA damage and inhibiting DNA repair [20], or by increasing apoptosis in radiation [21]. However, there are few studies about the effects of β-elemene on tumor microenvironment, and the effect on macrophages has not been reported yet.
In the present study, we investigated the influence of β-elemene on M2 macrophages in lung cancer cells and its effect on the phenotype of macrophages, to explore whether β-elemene could target TAMs in tumor therapy and to reveal a novel anti-tumor mechanism of β-elemene.
Section snippets
Reagents and antibodies
β-elemene was obtained from the National Institutes for Food and Drug Control (NIFDC; Beijing, China). 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) was purchased from Sigma (St. Louis, MO, USA). Polyclonal antibodies E-cadherin (20847-1-AP), Vimentin (10366-1-AP), N-cadherin (13769-1-AP), monoclonal antibody β-actin (60008-1-Ig) were obtained from ProteinTech (Chicago, IL, USA). Polyclonal antibody Arg-1(ab91279), monoclonal antibody iNOS (ab129372) were obtained from
β-elemene inhibits the conditioned medium of M2 macrophages induced migration and invasion of lung cancer cells
To investigate the effect of M2 macrophages on lung cancer cells and the effect of β-elemene on M2 macrophages. We treated RAW264.7 macrophages with IL-4 to induce them to differentiate to M2 phenotype. After stimulating with IL-4, RAW264.7 cells expressed higher levels of Arg-1 compared with untreated cells (Fig. 1a), suggesting that exposure to IL-4 successfully induced RAW264.7 cells to differentiate to M2 macrophages.
The half-maximal inhibitory concentration (IC50) of β-elemene for
Discussion
Tumor microenvironment (TME) is composed of malignant cells and stromal cells including immune cells, inflammatory cells, endothelial cells, fibroblasts and so on. Macrophages are the main inflammatory cells infiltrating tumor and their role in tumor growth and progression depends on their polarization (M1 vs. M2). M1 macrophages are pro-inflammatory, they can kill tumor cells directly, stimulate antitumor T-cells by secreting the pro-inflammatory cytokines, generate high level of iNOS, and are
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81473452).
References (30)
- et al.
Differential macrophage programming in the tumor microenvironment
Trends Immunol.
(2012) - et al.
Macrophage regulation of tumor responses to anticancer therapies
Cancer Cell
(2013) - et al.
Macrophage diversity enhances tumor progression and metastasis
Cell
(2010) - et al.
β-elemene induces glioma cell apoptosis by downregulating survivin and its interaction with hepatitis B X-interacting protein
Oncol. Rep.
(2012) - et al.
Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma
J. Hepatol.
(2015) - et al.
M2-polarized tumor-associated macrophages promoted epithelial–mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway
Lab. Invest
(2013) - et al.
The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock
Immunity
(2011) - et al.
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
Int. J. Cancer
(2015) - et al.
World Cancer Report 2014
(2014) - et al.
Coordinated regulation of myeloid cells by tumours
Nat. Rev. Immunol.
(2012)
The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies
J. Pathol.
Tumor-associated macrophages and survival in classic Hodgkin's lymphoma
N. Engl. J. Med.
β-elemene inhibited expression of DNA methyltransferase 1 through activation of ERK1/2 and AMPKalpha signalling pathways in human lung cancer cells: the role of Sp1
J. Cell Mol. Med.
Antiproliferative and apoptotic effects of beta-elemene on human hepatoma HepG2 cells
Cancer Cell Int.
Sensitization of lung cancer cells to cisplatin by β-elemene is mediated through blockade of cell cycle progression: antitumor efficacies of beta-elemene and its synthetic analogs
Med. Oncol.
Cited by (65)
Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy
2024, Acta Pharmaceutica Sinica BBeta-elemene: A phytochemical with promise as a drug candidate for tumor therapy and adjuvant tumor therapy
2024, Biomedicine and PharmacotherapyThe role of tumor-associated macrophages in lung cancer: From mechanism to small molecule therapy
2024, Biomedicine and PharmacotherapyThe complementary and alternative roles of elemene injection in cancer: An umbrella review
2023, Pharmacological ResearchPhytochemical-derived tumor-associated macrophage remodeling strategy using Phoenix dactylifera L. boosted photodynamic therapy in melanoma via H19/iNOS/PD-L1 axis
2023, Photodiagnosis and Photodynamic TherapyRole of macrophages in tumor development
2022, Recent Advancements in Microbial Diversity: Macrophages and their Role in Inflammation
- 1
These authors contributed equally to this work.