The induction of proapoptotic protein release through increased PTP formation and opening has been explored in the recent years as a possible mechanism for cancer treatment. As a chemotherapeutic approach, this method involves perturbation of the mitochondrial membrane through direct targeting of the components of the membrane permeability transition pore complex (PTPC) (Brenner et al., 2003; Costantini et al., 2000; Debatin et al., 2002; Fantin and Leder, 2006; Galluzzi et al., 2006; Khosravi-Far and Esposti, 2004; Morisaki and Katano, 2003; Reed, 2004). Additionally, alterations in energy metabolism, such as depletions in ADP and ATP, can also facilitate formation of the PTPC.
In addition to therapeutic strategies that target Bcl-2 family members, several chemotherapeutic agents such as paclitaxel or etopiside have been shown to induce opening of the PTPC, albeit at high concentrations. Additionally, several experimental anticancer agents act directly on the components of the PTPC. For example, the synthetic retinoid CD437, arsenic acid and lonidamine are inhibitors of ANT (Debatin et al., 2002; Fantin and Leder, 2006; Galluzzi et al., 2006). Arsenic acid also inhibits the VDAC. Hexokinase, which is a component of the PTPC and a major player in maintaining the malignant state of transformed cells, is also inhibited by lonidamine (Debatin et al., 2002; Fantin and Leder, 2006; Galluzzi et al., 2006). Additionally, jasmonates are known to act selectively and directly on cancer cell mitochondria in a PTPC-mediated mechanism, resulting in membrane depolarization, swelling, and the release of cytochrome c (Rotem et al., 2005) leading to apoptosis of tumor cells. Similarly, lamellarins are another group of anticancer drugs that target mitochondria of cancer cells and induce permeability transition effects (Kluza et al., 2006).
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