Photodynamic therapy with an endocytically located photosensitizer cause a rapid activation of the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun NH2 terminal kinase with opposing effects on cell survival

Weyergang, Anette; Kaalhus, Olav; Berg, Kristian

doi:10.1158/1535-7163.mct-08-0020

Cited by 29 publications

(25 citation statements)

References 34 publications

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“…In other studies using various photosensitizers, the role of p38 activation in PDT response appears to be ambiguous [29], [30], [31], [32], [33], [34]. Recently, p38 activation as a death signal has been described for the endocytically located photosensitizer TPPS2a (meso-tetraphenyl-porphine), which is applicable to photochemical internalization, a method used for release of endosomally/lysosomally trapped macromolecular drugs into the cell cytosol to enhance their biological effect in vitro [35]. We can relate our para EG-porphyrin results with these data because they exhibit similar intracellular localization and mechanism involving p38 MAPK activation in the cell death induction.…”

Section: Discussionmentioning

confidence: 99%

Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

Moserová

Králová

2012

PLoS ONE

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We have analyzed the molecular mechanisms of photoinduced cell death using porphyrins with similar structure differing only in the position of the ethylene glycol (EG) chain on the phenyl ring. Meta- and para-positioned EG chains targeted porphyrins to different subcellular compartments. After photoactivation, both types of derivatives induced death of tumor cells via reactive oxygen species (ROS). Para derivatives pTPP(EG)4 and pTPPF(EG)4 primarily accumulated in lysosomes activated the p38 MAP kinase cascade, which in turn induced the mitochondrial apoptotic pathway. In contrast, meta porphyrin derivative mTPP(EG)4 localized in the endoplasmic reticulum (ER) induced dramatic changes in Ca2+ homeostasis manifested by Ca2+ rise in the cytoplasm, activation of calpains and stress caspase-12 or caspase-4. ER stress developed into unfolded protein response. Immediately after irradiation the PERK pathway was activated through phosphorylation of PERK, eIF2α and induction of transcription factors ATF4 and CHOP, which regulate stress response genes. PERK knockdown and PERK deficiency protected cells against mTPP(EG)4-mediated apoptosis, confirming the causative role of the PERK pathway.

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Section: Discussionmentioning

confidence: 99%

Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

Moserová

Králová

2012

PLoS ONE

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“…The role of MAPK activation in PDT-related oxidative cell killing has been examined in a number of recent studies using different photosensitizing agents and tumor cell types (5,39-41). However, in contrast to other oxidative challenges (e.g.…”

Section: Discussionmentioning

confidence: 99%

Signaling events in apoptotic photokilling of 5-aminolevulinic acid-treated tumor cells: Inhibitory effects of nitric oxide

Bhowmick

Girotti

2009

Free Radical Biology and Medicine

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Antitumor photodynamic therapy (PDT) employs a photosensitizing agent, molecular oxygen, and visible light to produce reactive oxygen species that can destroy tumor and tumor vasculature cells. NO produced by these cells could be pro-carcinogenic by inhibiting apoptosis and promoting angiogenesis and tumor growth. We recently showed that NO from a chemical donor or activated macrophages makes COH-BR1 breast tumor cells more resistant to photokilling sensitized by 5-aminolevulinic acid (ALA)-generated protoporphyrin IX (PpIX). Signaling events associated with this hyperresistance have now been examined. ALA-treated COH-BR1 cells containing mitochondria-localized PpIX died mainly by apoptosis after being irradiated. Underlying redox signaling associated with MAP kinase (ERK1/2, p38, JUN) phosphorylation-activation and heme oxygenase-1 (HO-1) upregulation was studied using immunoprecipitation and Western blot methodology. ALA/light treatment resulted in activation of pro-apoptotic JNK and p38α, and deactivation of pro-survival p38β and ERK1/2. Involvement of both JNK and p38 in apoptosis was established by using a specific inhibitor for each. Spermine NONOate-derived NO, introduced immediately before irradiation, provided substantial protection against apoptosis. This was accompanied by greater HO-1 induction and strong inhibition of each MAP kinase effect seen in the absence of NO. Downstream of JNK and p38α activation, a marked upregulation/activation of proapoptotic Bax and Bid was observed along with down-regulation of anti-apoptotic Bcl-xL, each response being reversed by NO. These findings provide new insights into signaling activity associated with the intrinsic apoptotic pathway in ALA-PDT and how this activity can be modulated by NO.

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“…The therapeutic outcome of PCI may be influenced by PDT induced cellular signaling as inhibition or activation of selected signal pathways may influence on the cytotoxic effect of the drug delivered by PCI. We have found that TPPS 2a ‐PDT mediates death and survival signaling through ERK, p38, JNK, mTOR, and EGFR 84, 97, 98, and that some of these effects have impact on the outcome of PCI of gelonin 97. PDT generated protein signal transduction may also have an impact on PCI of targeted protein toxins, as indicated for PCI of cetuximab–saporin.…”

Section: Pci Of Targeted Protein Toxinsmentioning

confidence: 98%

Photochemical internalization of tumor-targeted protein toxins

et al. 2011

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Photochemical internalization (PCI) is a method for intracellular delivery of hydrophilic macromolecular drugs with intracellular targets as well as other drugs with limited ability to penetrate cellular membranes. Such drugs enter cells by means of endocytosis and are to a large extent degraded by hydrolytic enzymes in the lysosomes unless they possess a mechanism for cytosolic translocation. PCI is based on photodynamic therapy (PDT) specifically targeting the endosomes and lysosomes of the cells, so that the drugs in these vesicles can escape into the cytosol from where they can reach their targets. The preferential retention of the photosensitizer (PS) in tumor tissue in combination with controlled light delivery makes PCI relatively selective for cancer tissue. The tumor specificity of PCI can be further increased by delivery of drugs that selectively target the tumors. Indeed, this has been shown by PCI delivery of several targeted protein toxins. Targeted protein toxins may be regarded as ideal drugs for PCI delivery, and may represent the clinical future for the PCI technology.

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Photodynamic therapy with an endocytically located photosensitizer cause a rapid activation of the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun NH2 terminal kinase with opposing effects on cell survival

Cited by 29 publications

References 34 publications

Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

Signaling events in apoptotic photokilling of 5-aminolevulinic acid-treated tumor cells: Inhibitory effects of nitric oxide

Photochemical internalization of tumor-targeted protein toxins

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