Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells.

Abstract

Miltirone (1) is a diterpene quinone extracted from a well-known Chinese traditional herb (Salvia miltiorrhiza). We investigated the cytotoxic effects of miltirone toward sensitive and multidrug-resistant acute lymphoblastic leukemia cell lines. Miltirone inhibited multidrug-resistant P-glycoprotein (P-gp)-overexpressing CEM/ADR5000 cells better than drug-sensitive CCRF-CEM wild-type cells, a phenomenon termed collateral sensitivity. Flow cytometric analyses revealed that miltirone induced G2/M arrest and apoptosis. Furthermore, miltirone stimulated reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) disruption, which in turn induced DNA damage and activation of caspases and poly ADP-ribose polymerase (PARP). Downregulation of CCNB1 (cyclin B1) and CDC2 mRNA and upregulation of CDKN1A (p21) mRNA were in accord with miltirone-induced G2/M arrest. Moreover, miltirone decreased cell adherence to fibronectin. Molecular docking revealed that miltirone bound to the ATP-binding site of IKK-β. In conclusion, miltirone was collateral sensitive in multidrug-resistant P-gp-overexpressing cells, induced G2/M arrest, and triggered apoptosis via ROS-generated breakdown of MMP and DNA damage. Therefore, miltirone may be a promising candidate for cancer chemotherapy.

• Authors: Ching-Fen Wu, Thomas Efferth
• Journal: Journal of natural products (J Nat Prod) Vol. 78 Issue 6 Pg. 1339-47 (Jun 26 2015) ISSN: 1520-6025 [Electronic] United States
• PMID: 26035463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Cyclin-Dependent Kinase Inhibitor p21
• Phenanthrenes
• Reactive Oxygen Species
• miltirone
• Caspases

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Structure
• Phenanthrenes (chemistry, isolation & purification, pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Reactive Oxygen Species (metabolism)
• Salvia miltiorrhiza (chemistry)