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 conditions including skin cancer, involves the administration of a photosensitizing 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 and 6) network; and (ii) Rb/E2F-DP machinery during silicon phthalocyanine (Pc4)-PDT-mediated cell cycle dysregulation and apoptosis of human epidermoid carcinoma (A431) cells. Here, we investigated the involvement of EGFR-pathway during antiproliferative responses of Pc4-PDT in A431 cells and during ablation of murine skin papillomas. Pc4-PDT of A431 cells was found to result in a time-dependent down-modulation of the protein expression and phosphorylation of EGFR and Shc (an immediate downstream molecule in EGFR-pathway), during progressive increase in apoptotic response. To establish the relevance of these in vitro findings to in vivo situations, we subjected chemically- as well as ultraviolet B radiation-induced squamous papillomas in SENCAR and SKH-1 hairless mice, respectively, to Pc4-PDT, and assessed its effect 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 apoptosis, during the regression of these tumors. These data suggest the involvement of EGFR-pathway during the antiproliferative effects of PDT. It is tempting to speculate that inhibitors of EGFR could enhance the therapeutic efficacy of PDT.
Ahmad
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Department of Dermatology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
Kalka
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Mukhtar
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H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008812:Mice, Hairless; D018632:Mice, Inbred SENCAR; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
D007211:Indoles; D017319:Photosensitizing Agents; C107448:phthalocyanine Pc 4; D066246:ErbB Receptors