Mitochondrial voltage-dependent anion channels (VDACs) as novel pharmacological targets for anti-cancer agents.
Recently, it was demonstrated that some anti-cancer agents used mitochondrial voltage-dependent anion channels (VDAC1-3 isoforms) as their pharmacological target. VDACs are expressed more highly in cancer cells than normal cells; thus the VDAC-dependent cytotoxic agents can have cancer-selectivity. Furanonaphthoquinones (FNQs) induced caspase-dependent apoptosis via the production of NADH-dependent reactive oxygen species (ROS) by VDAC1. The ROS production and the anti-cancer activity of FNQs were increased by VDAC1 overexpression. Meanwhile, erastin induced RAS-RAF-MEK-dependent non-apoptotic cell death via VDAC2. On the other hand, VDACs were needed for transporting ATP to hexokinase (HK), which was highly expressed in cancer cells. We hypothesized that the high glycolysis might induce up-regulation of VDAC. In this review, we propose that VDACs are novel candidates for effective pharmacological targets of anti-cancer drugs.
Simamura
Eriko
E
Department of Molecular and Cell Structural Science, Kanazawa Medical University, Ishikawa, Uchinada, Japan. simamura@kanazawa-med.ac.jp
Shimada
Hiroki
H
Hatta
Toshihisa
T
Hirai
Kei-Ichi
K
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D050994:Voltage-Dependent Anion Channels; C477224:erastin; D048490:raf Kinases; D015689:Oncogene Protein p21(ras)