Cytotoxicity, apoptosis induction and downregulation of MDR-1 expression by the anti-topoisomerase II agent, salvicine, in multidrug-resistant tumor cells
✍ Scribed by Ze-Hong Miao; Tao Tang; Yi-Xiang Zhang; Jin-Sheng Zhang; Jian Ding
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- French
- Weight
- 332 KB
- Volume
- 106
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
Salvicine, a novel topoisomerase II inhibitor and a diterpenoid quinone compound, exerts potent in vitro and in vivo antitumor effects. In our study, we show that salvicine effectively kills multidrug‐resistant (MDR) sublines, such as K562/A02, KB/VCR and MCF‐7/ADR, and parental K562, KB and MCF‐7 cell lines to an equivalent degree. These cytotoxic activities of salvicine were much more potent than those of several classical anticancer drugs (average resistance factor: 1.42 for salvicine vs. 344.35, 233.19 and 71.22 for vincristine, doxorubicin and etoposide, respectively). Flow cytometry and DNA agarose gel electrophoresis demonstrated that salvicine induced similar levels of apoptosis in MDR K562/A02 and parental cells. The compound activated caspase‐1 and ‐3 (but not caspase‐8) and increased the ratio of bax to bcl‐2 mRNA via reduction of bcl‐2 mRNA expression in the same cells. Furthermore, salvicine induced the downregulation of mdr‐1 gene and P‐gp expression but had no effect on MRP and LRP gene expression in MDR K562/A02 cells. These results suggest that the reduction of mdr‐1 and bcl‐2 expression by salvicine possibly contributes to its cytotoxicity and apoptotic induction in this system. The effectiveness, broad‐spectrum activity and possibly novel mechanism of killing MDR tumor cells in vitro of salvicine signify promising in vivo and clinical activity. The novel chemical structure of this compound further implies a role for salvicine in future MDR tumor therapy. © 2003 Wiley‐Liss, Inc.