Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, and Christian-Albrechts-University, Kiel, Germany.
Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, University Hospital, LMU Munich, Munich, Germany.
Mol Cancer Ther. 2022 Jan;21(1):70-78. doi: 10.1158/1535-7163.MCT-21-0119. Epub 2021 Nov 1.
P8-D6 is a novel dual inhibitor of human topoisomerase I (TOP1) and II (TOP2) with broad pro-apoptotic antitumor activity. NCI-60 screening revealed markedly improved cytotoxicity of P8-D6 against solid and leukemia cell lines compared with other single and dual topoisomerase inhibitors, for example, irinotecan, doxorubicin, or pyrazoloacridine. In this study, we investigated the capacity of P8-D6 to inhibit myeloma cell growth and Growth inhibition assays demonstrated significant anti-myeloma effects against different myeloma cell lines with IC values in the low nanomolar range. Freshly isolated plasma cells of patients with multiple myeloma were killed by P8-D6 with similar doses. P8-D6 activated caspase 3/7 and induced significant apoptosis of myeloma cells. Supportive effects of bone marrow stromal cells on IL6-dependent INA-6 myeloma cells were abrogated by P8-D6 and apoptosis occurred in a time- and dose-dependent manner. Of note, healthy donor peripheral blood mononuclear cells and human umbilical vein endothelial cells were not affected at concentrations toxic for malignant plasma cells. Treatment of myeloma xenografts in immunodeficient SCID/beige mice by intravenous and, notably, also oral application of P8-D6 markedly inhibited tumor growths, and significantly prolonged survival of tumor-bearing mice.
P8-D6 是一种新型的人拓扑异构酶 I（TOP1）和 II（TOP2）双重抑制剂，具有广泛的促凋亡抗肿瘤活性。NCI-60 筛选显示，与其他单靶点和双靶点拓扑异构酶抑制剂（如伊立替康、阿霉素或吡唑并吖啶）相比，P8-D6 对实体瘤和白血病细胞系的细胞毒性有明显改善。在这项研究中，我们研究了 P8-D6 抑制骨髓瘤细胞生长的能力。生长抑制实验表明，P8-D6 对不同骨髓瘤细胞系具有显著的抗骨髓瘤作用，IC 值在低纳摩尔范围内。来自多发性骨髓瘤患者的新鲜分离的浆细胞也被 P8-D6 以相似的剂量杀死。P8-D6 激活了半胱天冬酶 3/7，并诱导骨髓瘤细胞发生明显的凋亡。P8-D6 还阻断了骨髓基质细胞对依赖 IL6 的 INA-6 骨髓瘤细胞的支持作用，凋亡呈时间和剂量依赖性。值得注意的是，在对恶性浆细胞有毒的浓度下，健康供体外周血单核细胞和人脐静脉内皮细胞不受影响。P8-D6 静脉内和口服应用于免疫缺陷 SCID/beige 小鼠的骨髓瘤异种移植，显著抑制肿瘤生长，并显著延长荷瘤小鼠的存活时间。
