Dimethyl Sulfoxide Suppresses Mouse 4T1 Breast Cancer Growth by Modulating Tumor-Associated Macrophage Differentiation.

Purpose: The universal organic solvent dimethyl sulfoxide (DMSO) can be used as a differentiation inducer of many cancer cells and has been widely used as a solvent in laboratories. However, its effects on breast cancer cells are not well understood. The aim of this study is to investigate the effect and associated mech­ anisms of DMSO on mouse breast cancer. Methods: We applied DMSO to observe the effect on tumors in a mouse breast cancer model. Tumor­associated macrophages (TAMs) were tested by flow cytometry. Ex vivo tumor microenvironment was imitated by 4T1 cultured cell conditioned medium. Enzyme­linked immuno­ sorbent assays were performed to detect interleukin (IL)­10 and IL­12 expression in medium. To investigate the cytotoxicity of DMSO on TAMs, 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazo­ lium bromide (MTT) assays were performed. Results: We found that DMSO produced tumor retardation when injected into mouse peritoneal cavities in a certain concentration range (0.5–1.0 mg/ g). Furthermore, as detected by flow cytometry, TAM subtypes were found to be transformed. We further imitated a tumor mi­ croenvironment in vitro by using 4T1 cultured cell conditioned medium. Similarly, by using low concentration DMSO (1.0%– 2.0% v/v), TAMs were induced to polarize to the classically acti­ vated macrophage (M1­type) and inhibited from polarizing into the alternatively activated macrophage (M2­type) in the condi­ tioned medium. IL­10 expression in tumors was reduced, while IL­12 was increased compared with the control. Furthermore, we reported that 2.0% (v/v) DMSO could lead to cytotoxicity in peri­ toneal macrophages after 48 hours in MTT assays. Conclusion: Our findings suggest that DMSO could exert antitumor effects in 4T1 cancer­bearing mice by reversing TAM orientation and po­ larization from M2­ to M1­type TAMs. These data may provide novel insight into studying breast cancer immunotherapy.