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Up-Regulation of Clusterin during Phthalocyanine 4 Photodynamic Therapy-mediated Apoptosis of Tumor Cells and Ablation of Mouse Skin Tumors¹

Departments of Dermatology [K. K., N. A., H. M.] and Radiation Oncology [T. C., D. B., H. M.], Case Western Reserve University, Cleveland, Ohio 44106

Photodynamic therapy (PDT) using the silicon phthalocyanine photosensitizer Pc 4 is an oxidative stress associated with the induction of apoptosis in many cancer cells in vitro and in vivo. The mechanisms of PDT-induced tumor cell killing leading to apoptosis are incompletely understood. Clusterin, a widely expressed glycoprotein, is induced in tissues regressing as a consequence of oxidative stress-mediated cell death. Treatment of apoptosis-sensitive human epidermoid carcinoma cells (A431) with PDT resulted in significant up-regulation of clusterin with a maximum at 12 h after treatment, whereas clusterin levels in Pc 4-PDT-treated, apoptosis-resistant, radiation-induced fibrosarcoma (RIF-1) cells remained unchanged. The i.v. administration of Pc 4 to mice bearing chemically or UVB radiation-induced skin papillomas, followed by light application, led to increased clusterin protein expression, peaking 24 h after the treatment, when tumor regression was apparently visible. These data, for the first time, demonstrate the involvement of clusterin in PDT-mediated cell death and during tumor regression. This may have relevance in improving the efficacy of PDT using pharmacological inducers of clusterin.

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