Mitochondrial permeability transition induced by the anticancer drug etoposide

• Author(s): Custódio, J. B. A. ; Cardoso, C. M. P. ; Madeira, V. M. C. ; Almeida, L. M.
• Date: 2001
• Persistent ID: http://hdl.handle.net/10316/5799
• Origin: Estudo Geral - Universidade de Coimbra
• Subject(s): Etoposide; Anticancer; Apoptosis; Liver mitochondria; Mitochondrial permeability transition
• Document Type: Article
• Language: English

Description

Etoposide (VP-16) is widely used for the treatment of several forms of cancer. The cytotoxicity of VP-16 has been assigned to the induction of apoptotic cell death but the signaling pathway for VP-16-induced apoptosis is essentially unknown. There is some evidence that this process depends on events associated with the loss of mitochondrial membrane potential ([Delta][Psi]) and/or release of apoptogenic factors, putatively as a consequence of mitochondrial permeability transition (MPT) induction. This work evaluates the interference of VP-16 with MPT in vitro, which is characterized by the Ca2+-dependent depolarization of [Delta][Psi], the release of matrix Ca2+ and by extensive swelling of mitochondria. [Delta][Psi] depolarization and Ca2+ release were measured with ion-selective electrodes, and mitochondrial swelling was monitored spectrophotometrically. Incubation of rat liver mitochondria with VP-16 results in a concentration-dependent induction of MPT, evidenced by an increased sensitivity to Ca2+-induced swelling, depolarization of [Delta][Psi], Ca2+ release by mitochondria and stimulation of state 4 oxygen consumption. All of these effects are prevented by preincubating the mitochondria with cyclosporine A, a potent and specific inhibitor of the MPT. Therefore, VP-16 increases the sensitivity of isolated mitochondria to the Ca2+-dependent induction of the MPT. Together, these data provide a possible mechanistic explanation for the previously reported effects of VP-16 on apoptosis induction. http://www.sciencedirect.com/science/article/B6TCP-440BK3X-3/1/13f3c58c1e8437ebdd53d792afd78b91