In vitro and in vivo inhibition of epidermal growth factor receptor-tyrosine kinase pathway by photodynamic therapy

PDT, a new therapeutic procedure for the management of many malignant condi tions including skin cancer, involves the administration of a photosensitiz ing compound followed by illumination of the lesion with visible light, We earlier showed an involvement of: (i) WAF1/ p21-cyclins (D1 and E)-cdk (2 a nd 6) network; and (ii) Rb/E2F-DP machinery during silicon phthalocyanine ( Pc4)-PDT-mediated cell cycle dysregulation and apoptosis of human epidermoi d carcinoma (A431) cells, Here, we investigated the involvement of EGFR-pat hway during antiproliferative responses of Pc4-PDT in A431 cells and during ablation of murine skin papillomas. Pc4-PDT of A431 cells was found to res ult in a time-dependent down-modulation of the protein expression and phosp horylation of EGFR and Shc (an immediate downstream molecule in EGFR-pathwa y), during progressive increase in apoptotic response. To establish the rel evance of these in vitro findings to in vivo situations, we subjected chemi cally- as well as ultraviolet B radiation-induced squamous papillomas in SE NCAR and SKH-1 hairless mice, respectively, to Pc4-PDT, and assessed its ef fect on EGFR-pathway during ablation of these tumors. Pc4-PDT was found to result in a time-dependent: (i) inhibition of protein expressions of EGFR; and (ii) tyrosine phosphorylation of EGFR and Shc; and (iii) induction of a poptosis, during the regression of these tumors, These data suggest the inv olvement of EGFR-pathway during the antiproliferative effects of PDT, It is tempting to speculate that inhibitors of EGFR could enhance the therapeuti c efficacy of PDT.