Abstract
There are many types of nontumor cells, including leukocytes, fibroblasts, and endothelial cells, in the tumor microenvironment. Among these cells, infiltrating macrophages have recently received attention as novel target cells due to their protumoral functions. Infiltrating macrophages are called tumor-associated macrophages (TAMs). TAMs polarized to the M2 phenotype are involved in tumor development and are associated with a poor clinical prognosis. Therefore, the regulation of TAM activation or M2 polarization is a new strategy for antitumor therapy. We screened natural compounds possessing an inhibitory effect on the M2 polarization of human macrophages. Among 200 purified natural compounds examined, corosolic acid (CA) and oleanolic acid (OA), both are categorized in triterpenoid compounds, inhibited macrophage polarization to M2 phenotype by suppressing STAT3 activation. CA and OA also directly inhibited tumor cell proliferation and sensitized tumor cells to anticancer drugs, such as adriamycin and cisplatin. The in vivo experiments showed that CA significantly suppressed subcutaneous tumor development and lung metastasis in a murine sarcoma model. The application of triterpenoid compounds, such as CA and OA, is a potential new anticancer therapy targeting macrophage activation, with synergistic effects with anticancer agents.
Highlights
Macrophages, first identified to be large phagocytes, play a critical role in innate and adaptive immunity by engulfing bacteria and other microbes and secreting several inflammatory molecules
signal transducer and activator of transcription 3 (STAT3) is considered to be an important target molecule for anticancer therapy, and many researchers have far reported the importance of various STAT3 inhibitors in the setting of anticancer therapy [56]
Natural compounds, such as corosolic acid (CA) and oleanolic acid (OA), exert inhibitory effects on STAT3 activation in macrophages, myeloid-derived suppressor cells (MDSCs), and tumor cells [29, 57, 58]. We revealed that those compounds inhibit tumor proliferation and differentiation of macrophages toward M2 phenotype via inhibiting STAT3 activation, whereas inhibitory mechanism of those compounds on MDSCs function has not been unclear
Summary
Macrophages, first identified to be large phagocytes, play a critical role in innate and adaptive immunity by engulfing bacteria and other microbes and secreting several inflammatory molecules. It has been reported that binding of the Hb-Hp complex to CD163-bearing cells elicits potent interleukin-10 secretion and the HO-1 expression [27, 28] These data indicate that CD163 is actively involved in the anti-inflammatory function of M2 macrophages, the precise ligand receptor effector pathway has not yet been clarified. The tumor cell culture supernatant (TCS) of the U373 glioblastoma cell line induces the upregulation of IL-10 secretion from macrophages [29] Among these compounds, CA and OA, triterpenoid compounds, were found to significantly suppress IL-10 secretion from LPS-stimulated macrophages (Figure 1(c)), whereas CA and OA caused no morphological changes or cytotoxic effects in the HMDMs (Figure 1(d)). These data indicate that CA and OA change M2 polarization to M1 polarization in HMDMs and regulate macrophage activation
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