Up-regulation of clusterin during phthalocyanine 4 photodynamic therapy-mediated apoptosis of tumor cells and ablation of mouse skin tumors

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 ill vivo. The mechanisms of PDT-induced tumo r cell killing leading to apoptosis are incompletely understood. Clusterin, a widely expressed glycoprotein, is induced in tissues regressing as a con sequence of oxidative stress-mediated cell death. Treatment of apoptosis-se nsitive human epidermoid carcinoma cells (A431) with PDT resulted in signif icant up-regulation of clusterin with a maximum at 12 h after treatment, wh ereas clusterin levels in Pc 4-PDT-treated, apoptosis-resistant, radiation- induced fibrosarcoma (RIF-1) cells remained unchanged. The i.v, administrat ion of Pc 4 to mice bearing chemically or UVB radiation-induced skin papill omas, followed by light application, led to increased clusterin protein exp ression, peaking 24 h after the treatment, when tumor regression was appare ntly visible, These data, for the first time, demonstrate the involvement o f clusterin in PDT-mediated cell death and during tumor regression. This ma y have relevance in improving the efficacy of PDT using pharmacological ind ucers of clusterin.