Shen Huan, Sun Changquan Calvin, Kang Lichun, Tan Xiaoyue, Shi Peng, Wang Lingyu, Liu Ergang, Gong Junbo
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China.
Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Eur J Pharm Sci. 2021 Feb 1;157:105629. doi: 10.1016/j.ejps.2020.105629. Epub 2020 Nov 8.
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.
巨噬细胞是免疫系统的哨兵，常常被肿瘤细胞劫持以协助肿瘤生长和转移。在此，我们的结果表明，10 - 50 nM范围内的低剂量沙利霉素（SAL）能够在体外以剂量和时间依赖性方式有效诱导M1巨噬细胞极化，30 nM SAL是从RAW246.7细胞产生M1型巨噬细胞的最佳浓度。在动物研究中，与PBS组相比，瘤内注射SAL（50 µg/kg）使移植4T1肿瘤中CD86细胞比例增加（28.9%），CD206细胞比例降低（14.2%）。因此，SAL组肿瘤生长显著消退（肿瘤抑制率达20%），肺转移减少（转移结节数量减少58%），而脂多糖（LPS）组和紫杉醇（PTX）组的转移灶数量和肿瘤体积相当。LPS治疗与SAL组一样也会导致肿瘤炎症反应，但会引发全身炎症（血清中IL - 1α、IL - 1β和TNF - α水平升高），且PTX（10 μg/kg）治疗会使两种类型的巨噬细胞均增加。我们首次发现，低于直接抗肿瘤活性剂量的沙利霉素能够有效启动M1型巨噬细胞刺激并使肿瘤生长和转移消退。
