Low-dose salinomycin inhibits breast cancer metastasis by repolarizing tumor hijacked macrophages toward the M1 phenotype

• Published in: European journal of pharmaceutical sciences 2021-02, Vol.157, p.105629-105629, Article 105629
• Main Authors: Shen, Huan, Sun, Changquan Calvin, Kang, Lichun, Tan, Xiaoyue, Shi, Peng, Wang, Lingyu, Liu, Ergang, Gong, Junbo
• Format: Article
• Language: English
• Subjects: breast cancer; dose-dependent effect; inflammation; macrophage polarization; pulmonary metastasis; Salinomycin
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2020.105629

lM1 macrophage polarization has become a hot therapeutic target in cancer research, but uncontrolled M1 activation may induce systemic inflammation and promote metastasislCancer researches on salinomycin all attributes the antitumor effects to its specific activity on cancer stem cells (CSCs), overlooking the fundamental roles of macrophage played in tumor metastasislLow dose salinomycin below the concentration of CSC activity, can prime M1 polarization of tumor associated macrophages and inhibited progression of orthotopic 4T1 breast cancer both in vitro and in vivo.lLow dose salinomycin induce local antitumor inflammations, without triggering systemic inflammation. [Display omitted] Macrophages are sentinels of the immune system, which are often hijacked by tumor cells to assist tumor growth and metastasis. Herein our results showed that low dose salinomycin (SAL) in the range of 10-50 nM could efficiently induce M1 macrophage polarization in a dose- and time- dependent manner in vitro, with 30 nM SAL being optimal to generate M1-type macrophages from RAW246.7 cells. In animal study, intratumorally injected SAL (50 µg/kg) increased proportion of CD86 cells (by 28.9%), and decreased CD206 cells (by 14.2%) in transplant 4T1 tumors, in comparison with PBS group. Thus it resulted in significant regression in tumor growth (20% tumor inhibition) and pulmonary metastasis (reduced the number of metastatic nodes by 58%) in SAL group, whereas lipopolysaccharide (LPS) and paclitaxel (PTX) groups showed comparable number of metastatic lesions and volume of tumor. LPS treatment could as well lead to inflammatory reactions in tumor with SAL group, but resulted in systemic inflammation (elevated levels of IL-1α, IL-1β and TNF-α in serum), and PTX (10 μg/kg) treatment increased both types of macrophages. For the first time, we employed salinomycin below the dose of direct antitumor activity could effectively prime M1 type macrophage stimulation and regress tumor growth and metastasis.