β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer

Highlights

• β-elemene inhibits M2 macrophages induced migration and invasion of cancer cells.

• β-elemene inhibits M2 macrophages induced EMT in lung cancer cells.

• β-elemene transforms macrophages from M2 to M1 phenotype.

• This study reveals a novel anti-tumor mechanism of β-elemene.

Abstract

Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy.

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.