Ruthenium red-mediated suppression of Bcl-2 loss and Ca2+ release initiated by photodamage to the endoplasmic reticulum: scavenging of reactive oxygen species

Kessel, David; Castelli, Michelle; Reiners, John J.

doi:10.1038/sj.cdd.4401579

Cited by 44 publications

(40 citation statements)

References 45 publications

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“…The ER is a known repository of calcium ions [16], and it seemed possible that ER photodamage might release sufficient Ca 2+ to result in interactions with the mitochondrial matrix that would lead to apoptosis. A study of the effect of ER photodamage on calcium fluxes [17] revealed several unexpected results.…”

Section: Apoptotic Responses To Pdt: the Role Of Bcl-2mentioning

confidence: 99%

Death pathways associated with photodynamic therapy

Kessel

2006

Medical Laser Application

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When the mitochondria and/or the endoplasmic reticulum were targeted by photodynamic therapy, photodamage to the anti-apoptotic protein Bcl-2 was observed. This led to an apoptotic outcome if that death pathway was available. Lysosomal photodamage ultimately resulted in activation of the pro-apoptotic protein Bid, also leading to apoptosis. Photodamage to the plasma membrane was associated with migration of sensitizers to the cytosol and procaspase photodamage, with apoptosis impaired. Where apoptosis was unavailable because of lack of necessary components of the program, an autophagic outcome has been observed. It is also clear that autophagy can occur along with apoptosis as a PDT response, and may play a role in immunologic responses to photodamaged tumor cells.

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Section: Apoptotic Responses To Pdt: the Role Of Bcl-2mentioning

confidence: 99%

Death pathways associated with photodynamic therapy

Kessel

2006

Medical Laser Application

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“…We have now examined the ability of salubrinal to protect murine leukemia L1210 cells from another inducer of ER stress: photodamage mediated by a porphycene termed 'CPO' that binds to the ER [3]. Irradiation of cells containing CPO initiates apoptosis as a result of photodamage to the anti-apoptotic protein Bcl-2 associated with the ER [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we used two photosensitizing agents: the chlorin termed NPe6 is known to target lysosomes but not Bcl-2, and mediates apoptosis via activation of the pro-apoptotic protein Bid [11]. The porphycene CPO does target Bcl-2 associated with the ER [3]. Irradiation of cells containing NPe6 did not alter Bcl-2 levels (Fig.…”

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Protection of Bcl-2 by salubrinal

Kessel

2006

Biochemical and Biophysical Research Communications

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The drug salubrinal has been identified as an inhibitor of phosphatases that act on the eukaryotic translation initiation factor 2 subunit (eIF2α). The resulting maintenance of protein phosphorylation results in enhanced protection from the adverse effects of initiators of the unfolded protein response. We found that salubrinal can also interact with the anti-apoptotic protein Bcl-2, inhibiting binding of the non-peptidic antagonist HA14-1 and of a porphycene that can catalyze Bcl-2 photodamage. As a result, salubrinal offers protection from the apoptotic and autophagic effects that can result from loss of Bcl-2 function. KeywordsApoptosis; Autophagy; Bcl-2; Photodynamic; Salubrinal Promotion of eIF2α phosphorylation results in a halt in protein synthesis, permitting cells to recover from consequences of endoplasmic reticulum (ER) stress that can otherwise lead to apoptosis [1]. The drug salubrinal was identified as a selective inhibitor of phosphatases that act on eIF2α [2], thereby maintaining protein phosphorylation and offering protection from the adverse effects of ER stress, e.g., as induced by the drug tunicamycin.We have now examined the ability of salubrinal to protect murine leukemia L1210 cells from another inducer of ER stress: photodamage mediated by a porphycene termed 'CPO' that binds to the ER [3]. Irradiation of cells containing CPO initiates apoptosis as a result of photodamage to the anti-apoptotic protein Bcl-2 associated with the ER [3,4]. Effects of ER photodamage on other stress-related phenomena have not been characterized. We now report that salubrinal protects cells from the pro-apoptotic effect of ER photodamage, a phenomenon that is, however, not associated with effects on eIF2α phosphorylation. We then examined the possibility that salubrinal could protect Bcl-2 from photodamage.Additional studies were carried out using HA14-1, a non-peptidic antagonist of the antiapoptotic functions of Bcl-2 family proteins. A computer screening approach was used to identify this agent as a ligand for the surface pocket on the Bcl-2 protein [5]. If the protection offered by salubrinal from the pro-apoptotic effects of ER photodamage was associated with a direct protective effect on Bcl-2, we considered it possible that this drug might also protect Bcl-2 from both pro-apoptotic [6] Cells and maintenanceMurine leukemia L1210 cells were grown in Fisher's medium (Sigma-Aldrich) containing 10% horse serum and 1 mM glutamine, 1 mM mercaptoethanol, and gentamicin. Since, Fisher's medium is no longer commercially available, we supplemented the α-MEM formulation (Sigma-Aldrich) with MgCl 2 (45 mg/l), methionine (75 mg/l), phenylalanine (30 mg/l), valine (30 mg/l), and folic acid (9 mg/l). Clonogenic assays were used to determine loss of viability (LD 90 values) after a 60 min exposure to HA14-1. Serial dilutions of cell suspensions were plated on soft agar. After 7-9 day growth in a humidified chamber under 5% CO 2 , colonies were counted and compared with untreated control values. All such experime...

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“…3) and elsewhere (1) suggested that the porphycene CPO is initially bound to the ER. Because these data are only qualitative, it is difficult to assign definitive localization patterns solely on the basis of such studies.…”

Section: Discussionmentioning

confidence: 99%

Studies on the Sub-cellular Localization of the Porphycene CPO

Kessel¹,

Conley²,

Vicente³

et al. 2005

Photochem Photobiol

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This study was designed to provide more detailed information on the subcellular sites of binding of the porphycene, termed 9-capronyloxytetrakis (methoxyethyl) porphycene (CPO), with a fluorescence resonance energy transfer (FRET) technique. The proximity of CPO to two fluorescent probes was determined: nonyl acridine orange (NAO), a dye with specific affinity for the mitochondrial lipid cardiolipin, and dihexaoxacarbocyanine iodide (DiOC 6 ), an agent that labels the endoplasmic reticulum (ER). FRET spectra indicated energy transfer between DiOC 6 and CPO but no significant transfer between NAO and CPO. These results confirm data obtained by fluorescence microscopy, suggesting a similar pattern of subcellular localization by CPO and DiOC 6 but not by CPO and NAO. However, when cells containing CPO were irradiated and then loaded with NAO, FRET between the two fluorophores was observed. Hence, a relocalization of CPO can occur during irradiation. These data provide an explanation for recent studies on CPO-catalyzed photodamage to both ER and mitochondrial Bcl-2.

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Ruthenium red-mediated suppression of Bcl-2 loss and Ca2+ release initiated by photodamage to the endoplasmic reticulum: scavenging of reactive oxygen species

Cited by 44 publications

References 45 publications

Death pathways associated with photodynamic therapy

Death pathways associated with photodynamic therapy

Protection of Bcl-2 by salubrinal

Studies on the Sub-cellular Localization of the Porphycene CPO

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