Riccardin D, a novel macrocyclic bisbibenzyl, induces apoptosis of human leukemia cells by targeting DNA topoisomerase II.

Abstract

We studied the effect of riccardin D, a macrocyclic bisbibenzyl, which was isolated from the Chinese liverwort plant, on human leukemia cells and the underlying molecular mechanism. Riccardin D had a significant antiproliferative effect on human leukemia cell lines HL-60, K562 and its multidrug resistant (MDR) counterpart K562/A02 cells, but showed no effect on the topoisomerase-II-deficient HL-60/MX2 cells, as measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The pBR322 DNA relaxation assay revealed that riccardin D selectively inhibited the activity of topoisomerase II (topo II). The suppression of topo II activity by riccardin D was stronger than that of etoposide, a known topo II inhibitor. After treatment with riccardin D, nuclear extracts of leukemia K562 and K562/A02 cells left the majority of pBR322 DNA in a supercoiled form. Further examination showed that riccardin D effectively induced HL-60, K562 and K562/A02 apoptosis as evidenced by externalization of phosphatidylserine and formation of DNA ladder fragments. The activation of cytochrome c, caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase (PARP) was also enhanced, as estimated by Western blot analysis. By contrast, riccardin D was unable to induce apoptosis in the topoisomerase-II-deficient HL-60/MX2 cells, indicating that the induction of apoptosis by riccardin D was due to the inhibition of topo II activity. In addition, riccardin D was able to significantly decrease P-glycoprotein (P-gp) expression in K562/A02 cells. Taken together, our data demonstrate that riccardin D is a novel DNA topo II inhibitor which can induce apoptosis of human leukemia cells and that it has therapeutic potential for both regular and MDR strains of leukemia cells.

• Authors: Xia Xue, Xian-Jun Qu, Zu-Hua Gao, Cui-Cui Sun, Hui-Ping Liu, Cui-Rong Zhao, Yan-Na Cheng, Hong-Xiang Lou
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 1 Pg. 212-22 (Feb 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 20924640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• DNA, Superhelical
• Phenyl Ethers
• Phosphatidylserines
• Stilbenes
• Topoisomerase II Inhibitors
• riccardin D
• Cytochromes c
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9
• DNA Topoisomerases, Type II

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• DNA Fragmentation
• DNA Topoisomerases, Type II (metabolism)
• DNA, Superhelical (metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• HL-60 Cells
• Humans
• K562 Cells
• Leukemia (enzymology, genetics, pathology)
• Phenyl Ethers (pharmacology)
• Phosphatidylserines (metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Stilbenes (pharmacology)
• Time Factors
• Topoisomerase II Inhibitors (pharmacology)