Fukami Akiko, Iijima Kousuke, Hayashi Masahiko, Komiyama Kanki, Omura Satoshi
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Biochem Biophys Res Commun. 2002 Mar 8;291(4):1065-70. doi: 10.1006/bbrc.2002.6572.
Macrosphelide B (MSB), a 16-membered macrolide from Microsphaeropsis sp. FO-5050, inhibits adhesion of sialyl Lewis(x) (sLe(x))-expressing HL-60 cells to LPS-activated (E-selectin-expressing) human umbilical vein endothelial cells (HUVECs) in vitro. This study examines MSB effects on metastasis of B16/BL6 mouse melanoma cells (B16/BL6 cells) and L5178Y-ML mouse lymphoma cells in vivo and analyzes the MSB antimetastatic activity mechanism. When administered MSB at 20 mg/kg/day, lung metastatic nodules of B16/BL6 cells were significantly decreased (T/C = 45%). However, no inhibition of metastasis of L5178Y-ML cells to the spleen and liver was observed. Flow cytometry analysis showed that B16/BL6 cells expressed high levels of sLe(x) antigen, whereas expression on L5178Y-ML cells was low. Under in vitro conditions, B16/BL6 cells demonstrated a greater degree of adhesion to LPS-activated HUVECs than L5178Y-ML cells, but adhesion was significantly inhibited by MSB and sLe(x) antibody. Combined therapy of MSB and cisplatin (CDDP) induced remarkable lung metastasis inhibition without adverse effects of CDDP to the host. All these findings suggest that MSB suppresses lung metastasis of B16/BL6 cells by inhibiting cell adhesion to endothelial cells through the sLe(x) molecule.
大环球孢菌素B（MSB）是一种从微球拟茎点霉属FO - 5050菌株中提取的16元大环内酯类化合物，在体外可抑制表达唾液酸化路易斯x（sLe(x)）的HL - 60细胞与脂多糖激活的（表达E - 选择素的）人脐静脉内皮细胞（HUVECs）的黏附。本研究检测了MSB对B16/BL6小鼠黑色素瘤细胞（B16/BL6细胞）和L5178Y - ML小鼠淋巴瘤细胞体内转移的影响，并分析了MSB的抗转移活性机制。当以20 mg/kg/天的剂量给予MSB时，B16/BL6细胞的肺转移结节显著减少（T/C = 45%）。然而，未观察到对L5178Y - ML细胞向脾脏和肝脏转移的抑制作用。流式细胞术分析表明，B16/BL6细胞高水平表达sLe(x)抗原，而L5178Y - ML细胞上的表达较低。在体外条件下，B16/BL6细胞比L5178Y - ML细胞对脂多糖激活的HUVECs表现出更大程度的黏附，但MSB和sLe(x)抗体可显著抑制黏附。MSB与顺铂（CDDP）联合治疗可显著抑制肺转移，且无CDDP对宿主的不良反应。所有这些发现表明，MSB通过抑制细胞通过sLe(x)分子与内皮细胞的黏附来抑制B16/BL6细胞的肺转移。
