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.
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