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.
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Abbreviations
- CoQ0 :
-
Coenzyme Q0
- VDAC1:
-
Voltage‐dependent anion channel 1
- ΔΨ:
-
Mitochondrial membrane potential
- PTP:
-
Permeability transition pore
- ROS:
-
Reactive oxygen species
- NAC:
-
N-acetylcysteine
- MTT:
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- zVAD-FMK:
-
Z-Val-Ala-Asp-fluoromethylketone
- PI:
-
Propidium iodide
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Acknowledgements
This work was supported by the Grants MOST-104-2320-B-039-040-MY3, MOST-103-2320-B-039-038-MY3, and NSC-103-2622-B-039-001-CC2 from the Ministry of Science and Technology, National Science Council, Asia University and China Medical University, Taiwan. This study was supported by China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan (CHM106-5-3).
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Hseu, YC., Thiyagarajan, V., Ou, TT. et al. CoQ0-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. Arch Toxicol 92, 301–322 (2018). https://doi.org/10.1007/s00204-017-2050-6
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DOI: https://doi.org/10.1007/s00204-017-2050-6