CoQ 0 -induced mitochondrial PTP opening triggers apoptosis via ROS-mediated VDAC1 upregulation in HL-60 leukemia cells and suppresses tumor growth in athymic nude mice/xenografted nude mice

Abstract

Coenzyme Q (CoQ) analogs with variable numbers of isoprenoid units have been demonstrated as anticancer and antioxidant/pro-oxidant molecules. This study examined the in vitro and in vivo antitumor and apoptosis activities of CoQ₀ (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero isoprenoid side-chains) through upregulation of the Voltage‐dependent anion channel 1 (VDAC1) signaling pathway on human promyelocytic leukemia. CoQ₀ (0–40 μg/mL) treatment significantly reduced HL-60 cell viability, and up-regulated mitochondrial VDAC1 expression. CoQ₀ treatment triggers intracellular ROS generation, calcium release, ΔΨm collapse and PTP opening in HL-60 cells. CoQ₀ treatment induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-3 and PARP activation, and Bax/Bcl-2 dysregulation. Annexin V-PI staining indicated that CoQ₀ promotes late apoptosis. Furthermore, the blockade of CoQ₀-induced ROS production by antioxidant NAC pretreatment substantially attenuated CoQ₀-induced apoptosis. The activation of p-GSK3β expression, cyclophilin D inhibition, and p53 activation through ROS are involved in CoQ₀-induced HL-60 apoptotic cell death. Notably, ROS-independent p38 activation is involved in CoQ₀-mediated apoptosis in HL-60 cells. In addition, the silencing of VDAC1 also prevented CoQ₀-induced mitochondrial translocation of Bax, activation of caspase-3, and reduction in Bcl-2. Intriguingly, VDAC1 silencing did not prevent ROS production induced by CoQ₀, which in turn indicates that CoQ₀ induced ROS-mediated VDAC1 and then mitochondrial apoptosis in HL-60 cells. In vivo results revealed that CoQ₀ is effective in delaying tumor incidence and reducing the tumor burden in HL-60-xenografted nude mice. Taken together, CoQ₀ could be a promising anticancer agent for the treatment of human promyelocytic leukemia through upregulation of VDAC1 signaling pathways.