体内
体外
化学
癌症研究
拓扑异构酶
喜树碱
细胞凋亡
药理学
分子生物学
多发性骨髓瘤
细胞毒性
细胞培养
生物
细胞生长
MTT法
作者
Katja Klausz,Christian Kellner,Carina Lynn Gehlert,Steffen Krohn,Hauke Wilcken,Inken Floerkemeier,Andreas Guenther,Dirk Bauerschlag,Bernd Clement,Martin Gramatzki,Matthias Peipp
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2021-11-01
标识
DOI:10.1158/1535-7163.mct-21-0119
摘要
P8-D6 is a novel dual inhibitor of human topoisomerase I (TOP1) and II (TOP2) with broad pro-apoptotic anti-tumor activity. NCI-60 screening revealed markedly improved cytotoxicity of P8-D6 against solid and leukemia cell lines compared to other single and dual topoisomerase inhibitors, e.g. irinotecan, doxorubicin or pyrazoloacridine. In this study, we investigated the capacity of P8-D6 to inhibit myeloma cell growth in vitro and in vivo. Growth inhibition assays demonstrated significant anti-myeloma effects against different myeloma cell lines with IC50 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 IL-6-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 (PBMC) and human endothelial cells (HUVEC) 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI