Affiliations: Abteilung Pädiatrie I, Zentrum Kinderheilkunde und Jugendmedizin, Universitätsklinikum Göttingen, D-37075 Göttingen, Germany | Department of Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion–Israel Institute of Technology, Haifa, Israel
Note: [] Dr. Wilfried Kugler and Dr. Leo Veenman have equally contributed to this work.
Note: [] Dr. Wilfried Kugler and Dr. Leo Veenman have equally contributed to this work.
Note: [] Corresponding author: Prof. M. Gavish, Department of Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, P.O. Box 9649, Bat-Galim, Haifa 31096, Israel. Tel.: +972 4 8295276; Fax: +972 4 8295271; E-mail: [email protected].
Abstract: Background: We have previously shown that the anti-neoplastic agent erucylphosphohomocholine (ErPC3) requires the mitochondrial 18 kDa Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), to induce cell death via the mitochondrial apoptosis pathway. Methods: With the aid of the dye JC-1 and cyclosporin A, applied to glioblastoma cells, we now investigated the significance of opening of the mitochondrial permeability transition pore (MPTP) for ErPC3-induced apoptosis in interaction with the TSPO ligands, PK 11195 and Ro5 4864. Furthermore, we measured cytochrome c release, and caspase-9 and -3 activation in this paradigm. Results: The human glioblastoma cell lines, U87MG, A172 and U118MG express the MPTP-associated TSPO, voltage-dependent anion channel and adenine nucleotide transporter. Indeed, ErPC3-induced apoptosis was inhibited by the MPTP blocker cyclosporin A and by PK 11195 and Ro5 4864 in a concentration-dependent manner. Furthermore, PK 11195 and Ro5 4864 inhibited collapse of the mitochondrial membrane potential, cytochrome c release, and caspase-9 and -3 activation caused by ErPC3 treatment. Conclusions: This study shows that PK 11195 and Ro5 4864 inhibit the pro-apoptotic function of ErPC3 by blocking its capacity to cause a collapse of the mitochondrial membrane potential. Thus, the TSPO may serve to open the MPTP in response to anti-cancer drugs such as ErPC3.
