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Research Articles: Therapeutics, Targets, and Development

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

Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

Requests for reprints: Anette Weyergang, Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. Phone: 47-22-93-46-36; Fax: 47-22-93-42-70. E-mail: anette.weyergang{at}rr-research.no

Abstract

Photochemical internalization (PCI) is a method for release of endosomally/lysosomally trapped drugs into the cell cytosol. PCI is based on photosensitizers that accumulate in the membranes of endosomes and lysosomes. Light exposure generates reactive oxygen species that cause membrane rupture and subsequently drug release. PCI can be considered as a combination therapy of photodynamic therapy (PDT) and the administrated drug. The present work reports on mitogen-activated protein kinase signaling after PDT with the endocytically located photosensitizer TPPS_2a (meso-tetraphenylporphine with two sulfonate groups on adjacent phenyl rings) as used for PCI in two cancer cell lines: NuTu-19 and WiDr. Both extracellular signal-regulated kinase (ERK) and p38 were activated immediately after PDT. The photochemically induced ERK phosphorylation was enhanced by epidermal growth factor stimulation to a level above that obtainable with epidermal growth factor alone. Expression of the ERK phosphatase, MAPK phosphatase-1, was increased 2 h after PDT but was not the cause of ERK dephosphorylation observed simultaneously. A transient activation of c-Jun NH₂ terminal kinase was also observed after PDT but only in the NuTu-19 cells. Using suitable inhibitors, it is shown here that the p38 signal is a death signal, whereas c-Jun NH₂ terminal kinase rescues cells after PDT. No direct connection was observed between PDT-induced ERK activation and toxicity of the treatment. The present results document the importance of the mitogen-activated protein kinases in TPPS_2a-PDT-induced cytotoxicity. [Mol Cancer Ther 2008;7(6):1740–50]

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Received 1/ 8/08; revised 3/ 6/08; accepted 3/10/08.