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Mitochondrial Malfunctioning, Proteasome Arrest and Apoptosis in Cancer Cells by Focused Intracellular Generation of Oxygen Radicals

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy
Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Naples 80131, Italy
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Michael R. Hamblin and Ying-ying Huang
Int. J. Mol. Sci. 2015, 16(9), 20375-20391;
Received: 22 June 2015 / Revised: 10 August 2015 / Accepted: 21 August 2015 / Published: 28 August 2015
(This article belongs to the Special Issue Advances in Photodynamic Therapy)
PDF [1295 KB, uploaded 28 August 2015]


Photofrin/photodynamic therapy (PDT) at sub-lethal doses induced a transient stall in proteasome activity in surviving A549 (p53+/+) and H1299 (p53−/−) cells as indicated by the time-dependent decline/recovery of chymotrypsin-like activity. Indeed, within 3 h of incubation, Photofrin invaded the cytoplasm and localized preferentially within the mitochondria. Its light activation determined a decrease in mitochondrial membrane potential and a reversible arrest in proteasomal activity. A similar result is obtained by treating cells with Antimycin and Rotenone, indicating, as a common denominator of this effect, the ATP decrease. Both inhibitors, however, were more toxic to cells as the recovery of proteasomal activity was incomplete. We evaluated whether combining PDT (which is a treatment for killing tumor cells, per se, and inducing proteasome arrest in the surviving ones) with Bortezomib doses capable of sustaining the stall would protract the arrest with sufficient time to induce apoptosis in remaining cells. The evaluation of the mitochondrial membrane depolarization, residual proteasome and mitochondrial enzymatic activities, colony-forming capabilities, and changes in protein expression profiles in A549 and H1299 cells under a combined therapeutic regimen gave results consistent with our hypothesis. View Full-Text
Keywords: photodynamic therapy; Photofrin; Bortezomib; combination therapy; proteasome photodynamic therapy; Photofrin; Bortezomib; combination therapy; proteasome

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Postiglione, I.; Chiaviello, A.; Barra, F.; Roscetto, E.; Soriano, A.A.; Catania, M.R.; Palumbo, G.; Pierantoni, G.M. Mitochondrial Malfunctioning, Proteasome Arrest and Apoptosis in Cancer Cells by Focused Intracellular Generation of Oxygen Radicals. Int. J. Mol. Sci. 2015, 16, 20375-20391.

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