Zhu Haimei, Wang Yuji, Song Ce, Feng Qiqi, Wu Jianhui, Zhao Shurui, Gui Lin, Zhang Xiaoyi, Zhao Ming, Peng Shiqi
College of Pharmaceutical Sciences of Capital Medical University, Beijing, China.
Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing, China.
Oncotarget. 2017 Jul 19;9(1):268-281. doi: 10.18632/oncotarget.19374. eCollection 2018 Jan 2.
The impact of soluble P-selectin on tumor growth, thrombosis and inflammation has been individually documented. Whether the down-regulation of P-selectin expression can simultaneously slow the tumor growth, inhibit the thrombosis and attenuate the inflammatory response remains unknown. In this context, (2'S,5'S)- tetrahydropyrazino[1',2':1,6]-di{2,3,4,9-tetrahydro-1-pyrido[3,4-b]indole}-1',4'-dione (THPDTPI) was designed as an inhibitor of P-selectin. The suitable docking of THPDTPI towards the active site of P-selectin, the significant down-regulation of THPDTPI to P-selectin expression, and the direct action of THPDTPI on P-selectin suggest that P-selectin could be a target of THPDTPI. THPDTPI possesses the anti-tumor activity, the anti-thrombotic activity and the anti-inflammatory activity. This implies that targeting P-selectin is of essential importance for this triple activity. The minimal effective doses of THPDTPI inhibiting the tumor growth, the rat arterial thrombosis and the mouse ear edema are 0.01 μmol/kg, 0.1 μmol/kg and 0.001 μmol/kg, respectively. Atomic force microscopy images and FT-MS spectra showed that the adhesion of THPDTPI onto the surfaces of the platelets may be the first step of P-selectin targeting. Besides, the dependence of the triple action of THPDTPI inhibiting the tumor growth, the thrombosis and the inflammation on the decrease of the soluble P-selectin led to the correlation of the soluble P-selectin with the serum TNF-α and serum IL-8.
可溶性P-选择素对肿瘤生长、血栓形成和炎症的影响已有单独记录。P-选择素表达的下调是否能同时减缓肿瘤生长、抑制血栓形成并减轻炎症反应仍不清楚。在此背景下，设计了(2'S,5'S)-四氢吡嗪并[1',2':1,6]-二{2,3,4,9-四氢-1-吡啶并[3,4-b]吲哚}-1',4'-二酮（THPDTPI）作为P-选择素的抑制剂。THPDTPI与P-选择素活性位点的合适对接、THPDTPI对P-选择素表达的显著下调以及THPDTPI对P-选择素的直接作用表明P-选择素可能是THPDTPI的靶点。THPDTPI具有抗肿瘤活性、抗血栓活性和抗炎活性。这意味着靶向P-选择素对这种三重活性至关重要。THPDTPI抑制肿瘤生长、大鼠动脉血栓形成和小鼠耳部水肿的最小有效剂量分别为0.01 μmol/kg、0.1 μmol/kg和0.001 μmol/kg。原子力显微镜图像和傅里叶变换质谱光谱表明，THPDTPI在血小板表面的黏附可能是靶向P-选择素的第一步。此外，THPDTPI抑制肿瘤生长、血栓形成和炎症的三重作用对可溶性P-选择素降低的依赖性导致了可溶性P-选择素与血清TNF-α和血清IL-8的相关性。
