Resveratrol enhanced chemosensitivity by reversing macrophage polarization in breast cancer

Abstract

Background: Resveratrol is a naturally occurring polyphenolic compound in Polygonum cuspidatum and is well known for its antitumor effect by targeting several cancer-related inflammatory pathways. However, limited data is available on the effect of resveratrol in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant leukocyte population within the tumors and are associated with poor prognosis in over 80% of breast cancer cases. This study aimed to investigate the effect of resveratrol on TAM polarization in breast cancer progression. Methods: The antitumor effect of resveratrol was examined in MDA-MB-231(MB231), cisplatin resistance MDA-MB-231 (cisR) cells, and T47D by cell proliferation assay using MTT. Gene expressions of M1 and M2 markers in macrophages derived from THP-1 cells were examined by qPCR and immunofluorescence staining after treated with tumor-conditioned medium (TCM) with or without resveratrol (25μM). Cytokine profile of TCM was examined by Qiagen Multi-Analyte ELISArray and expression of cytokines in TCM was validated by qPCR and ELISA. The effect of resveratrol and its downstream targets on macrophage polarization were investigated by supplementing resveratrol with interferon gamma (IFN-γ, 20ng/ml) and lipopolysaccharide (LPS, 100ng/ml) for M1 macrophage polarization or IL-4 (20ng/ml) and IL-13 (20ng/ml)for M2 macrophage polarization. NOD/SCID mice were used to investigate the potential use of resveratrol in treating breast cancer and chemotherapy as complementary treatment in vivo. Results: Our preliminary data demonstrated that resveratrol significantly reduced cell proliferation and enhanced chemosensitivity in MB231, cisR, and T47D cells. Resveratrol inhibited CD163 (M2 marker) and increased CXCL10 (M1 marker) expression. In addition, resveratrol decreased exogenous IL-6 levels in TCM, thus inhibited breast cancer cell proliferation by promoting M1/M2 macrophage polarization ratio and supressing IL-6/pSTAT3 pathway. Combined use of resveratrol and cisplatin significantly decreased tumor size in vivo. Conclusion: Our data demonstrated that resveratrol enhanced chemosensitivity in vivo and in vitro by promoting M1/M2 macrophage polarization ratio and supressing STAT3 activation through reducing exogenous IL-6 levels. This study revealed a novel mechanism on resveratrol-mediated macrophage polarization on breast cancer progression.