Photochemical destruction of the Bcl-2 oncoprotein during photodynamic therapy with the phthalocyanine photosensitizer Pc 4

Xue, Liang-yan; Chiu, Song Mao; Oleinick, Nancy L.

doi:10.1038/sj.onc.1204441

Cited by 201 publications

(193 citation statements)

References 39 publications

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“…Photosensitization of murine leukemia L1210 cells with various sensitizers reduced Bcl-2 protein levels, without affecting Bax [59,96], as detected by Western Blot, and similar findings were reported for human breast cancer MCF-7 cells and DU-145 cells (human prostate cancer) sensitized with Pc 4 [55,95,97]. In the latter study, the protein levels of Bad were unchanged by PDT [97].…”

Section: Role Of the Bcl-2 Family Of Proteins In Pdtsupporting

confidence: 70%

Intracellular signaling mechanisms in photodynamic therapy

Almeida

Manadas

Carvalho

et al. 2004

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

242

292

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In photodynamic therapy (PDT) a sensitizer, light and oxygen are used to induce death of tumor cells and in the treatment of certain noncancerous conditions. Cell death in PDT may occur by apoptosis or by necrosis, depending on the sensitizer, on the PDT dose and on the cell genotype. Some sensitizers that have been used in PDT are accumulated in the mitochondria, and this may explain their efficiency in inducing apoptotic cell death, both in vitro and in vivo. In this review we will focus on the events that characterize apoptotic death in PDT and on the intracellular signaling events that are set in motion in photosensitized cells. Activation of phospholipases, changes in ceramide metabolism, a rise in the cytosolic free Ca 2 + concentration, stimulation of nitric oxide synthase (NOS), changes in protein phosphorylation and alterations in the activity of transcription factors and on gene expression have all been observed in PDT-treated cells. Although many of these metabolic reactions contribute to the demise process, some of them may antagonize cell death. Understanding the signaling mechanisms in PDT may provide means to modulate the PDT effects at the molecular level and potentiate its antitumor effectiveness. D

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Section: Role Of the Bcl-2 Family Of Proteins In Pdtsupporting

confidence: 70%

Intracellular signaling mechanisms in photodynamic therapy

Almeida

Manadas

Carvalho

et al. 2004

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

242

292

View full text Add to dashboard Cite

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“…Thus, the present data confirm that PDT induces apoptosis through this signalling pathway. However, although mitochondria have been shown to be a prime target of PDT with certain photosensitisers (Kessel and Luo, 1998), and PDT causes photodamage to mitochondrion-bound proteins, in particular Bcl-2 (Xue et al, 2001a) and Bcl-xL (Xue et al, 2003a), and to mitochondrial and endoplasmic reticulum membrane structure (Grebenova et al, 2003), the present data suggest that the photodamage is insufficient to cause the release of cytochrome c spontaneously through the outer mitochondrial membrane. The release needs the participation of Bax.…”

Section: Discussionmentioning

confidence: 50%

Bax is essential for mitochondrion-mediated apoptosis but not for cell death caused by photodynamic therapy

et al. 2003

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The role of Bax in the release of cytochrome c from mitochondria and the induction of apoptosis has been demonstrated in many systems. Using immunocytochemical staining, we observed that photodynamic therapy (PDT) with the photosensitiser Pc 4 induced Bax translocation from the cytosol to mitochondria, and the release of cytochrome c from mitochondria as early signalling for the intrinsic pathway of apoptosis in human breast cancer MCF-7c3 cells. To test the role of Bax in apoptosis, MCF-7c3 cells were treated with Bax antisense oligonucleotides, which resulted in as much as a 50% inhibition of PDT-induced apoptosis. In the second approach, Bax-negative human prostate cancer DU-145 cells were studied. Following PDT, the hallmarks of apoptosis, including the release of cytochrome c from mitochondria, loss of mitochondrial membrane potential, caspase activation, and chromatin condensation and fragmentation, were completely blocked in these cells. Restoration of Bax expression in DU-145 cells restored apoptosis, indicating that the resistance of DU-145 cells to PDT-induced apoptosis is due to the lack of Bax rather than to another defect in the apoptotic machinery. However, despite the inhibition of apoptosis, the Bax-negative DU-145 cells were as photosensitive as Bax-replete MCF7c3 cells, as determined by clonogenic assay. Thus, for Pc 4-PDT, the commitment to cell death occurs prior to Bax activation.

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“…Locally generated ROS might then act on mitochondrial PTPC components, including VDAC and ANT, and cause the formation of protein-permeable conduits or nonspecific ion channels (Belzacq et al, 2001b). The photosensitizer hypericin reportedly detaches hexokinase from mitochondria (Miccoli et al, 1998), whereas the phthalocyanine photosensitizer Pc 4 causes the photochemical destruction of Bcl-2 (Xue et al, 2001). Altogether, available data suggest that photosensitizing agents can target mitochondria, where they induce apoptosis independently from the p53 status, even in Bax-negative cells (Chiu et al, 2005).…”

Section: Chemotherapy and Mitochondriamentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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Photochemical destruction of the Bcl-2 oncoprotein during photodynamic therapy with the phthalocyanine photosensitizer Pc 4

Cited by 201 publications

References 39 publications

Intracellular signaling mechanisms in photodynamic therapy

Intracellular signaling mechanisms in photodynamic therapy

Bax is essential for mitochondrion-mediated apoptosis but not for cell death caused by photodynamic therapy

Mitochondria as therapeutic targets for cancer chemotherapy

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