Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent

作者：Zhu, Haimei; Wang, Yuji; Song, Ce^*; Feng, Qiqi; Wu, Jianhui; Zhao, Shurui; Gui, Lin; Zhang, Xiaoyi; Zhao, Ming^*; Peng, Shiqi^*

来源：Oncotarget, 2018, 9(1): 268-281.

DOI：10.18632/oncotarget.19374

• selectin
• anti-tumor
• anti-thrombosis
• anti-inflammation
• target

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-1H-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. In vivo 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 mu mol/kg, 0.1 mu mol/kg and 0.001 mu mol/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-alpha and serum IL-8.

• 出版日期2018-1-2
• 单位首都医科大学