Mitochondrial voltage-dependent anion channels (VDACs) as novel pharmacological targets for anti-cancer agents Eriko Simamura & Hiroki Shimada & Toshihisa Hatta & Kei-Ichi Hirai Published online: 15 August 2008 # Springer Science + Business Media, LLC 2008 Abstract 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. Keywords Mitochondria . Voltage-dependent anion channel (VDAC) . Pharmacological target . Anti-cancer agent . Apoptosis . Reactive oxygen species (ROS) . Adenine nucleotide translocator . Hexokinase Introduction In cancer therapy, it is important to determine whether anti- cancer drugs can discriminate between cancer cells and normal cells. Hence, a wide variety of oncogenes have been studied, and anti-cancer drugs with oncogenes-selective lethality have been developed. Voltage-dependent anion channels (VDAC1–3 isoforms), which are located in the mitochondrial outer membrane, have been studied mainly as one of the requisite actors for mitochondrial-dependent apoptosis. VDACs have been studied as one of the mediators of the mitochondrial permeability transition induced by Ca 2+ overload (Shimizu et al. 2001) and oxidative damage (Madesh and Hajnoczky 2001). Recently, some groups reported focusing on VDACs as the pharmacologic target for novel molecules inducing cancer cell death. In this review we first overview the functions of the VDAC family proteins, including the difference in the expression of VDACs between cancer and normal cells. Then, we categorize VDAC-dependent cytotoxic agents into three groups: (1) VDAC1-dependent chemicals, which induced caspase-dependent apoptosis by the production of reactive oxygen species (ROS) (Hirai et al. 1999; Pan et al. 2000; Simamura et al. 2003, 2006); (2) VDAC2 and/or VDAC3-dependent chemicals, which induced RAS-RAF- MEK-dependent oxidative cell death (Yagoda et al. 2007); and (3) phosphorothioate antisense oligonucleotide, which induced caspase-dependent apoptosis (Lai et al. 2006; Tan et al. 2007a, b). Finally, we discuss the cancer-selective VDAC activity in conjunction with other mitochondrial channels and hexokinase II (HK II) in cancer cells. VDAC family proteins Mitochondrial VDAC was found to be located in the mitochondrial outer membrane and to form the pores of the outer membrane (Colombini 1980). At least 2 human VDAC isoforms were found to be present (Blachly-Dyson J Bioenerg Biomembr (2008) 40:213–217 DOI 10.1007/s10863-008-9158-6 E. Simamura (*) : H. Shimada : T. Hatta : K.-I. Hirai Department of Molecular and Cell Structural Science, Kanazawa Medical University, Ishikawa, Uchinada 920-0293, Japan e-mail: simamura@kanazawa-med.ac.jp