Mitochondrial Malfunctioning, Proteasome Arrest and Apoptosis in Cancer Cells by Focused Intracellular Generation of Oxygen Radicals.
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.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. ilariapostiglione@gmail.com.
Ilaria
I
Postiglione
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. angelachiaviello@libero.it.
Angela
A
Chiaviello
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. federica.barra@unina.it.
Federica
F
Barra
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. emanuelaroscetto@gmail.com.
Emanuela
E
Roscetto
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. amata.soriano@libero.it.
Amata A
AA
Soriano
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. mariarosaria.catania@unina.it.
Maria Rosaria
MR
Catania
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. palumbo@unina.it.
Giuseppe
G
Palumbo
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy. giovannamaria.pierantoni@unina.it.|Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Naples 80131, Italy. giovannamaria.pierantoni@unina.it.
Giovanna Maria
GM
Pierantoni
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D017323:Dihematoporphyrin Ether / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D017323:Dihematoporphyrin Ether; D046988:Proteasome Endopeptidase Complex
Bortezomib; Photofrin; combination therapy; photodynamic therapy; proteasome