Targeting the 90 kDa heat shock protein improves photodynamic therapy.
The geldanamycin derivative, 17-allylamino-17-demethoxygeldanamycin (17-AAG), binds to the amino-terminal ATP binding pocket of the 90 kDa heat shock protein (Hsp-90) and inhibits this chaperone from stabilizing client proteins involved with the malignant phenotype. We examined the effects of a combined modality protocol involving photodynamic therapy (PDT) and 17-AAG in mouse mammary carcinoma cells and tumors. PDT increased the expression of the anti-apoptotic and pro-angiogenic proteins survivin, Akt, HIF-1alpha, MMP-2 and VEGF in tumor tissue and this expression decreased significantly when 17-AAG was included in the treatment regimen. Tumor bearing mice treated with PDT and 17-AAG had improved long-term tumoricidal responses when compared with individual treatment protocols. We conclude that Hsp-90 plays an active role in modulating tumor responsiveness following PDT and targeting Hsp-90 with 17-AAG enhances the therapeutic effectiveness of PDT.
Ferrario
Angela
A
The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Gomer
Charles J
CJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016227:Benzoquinones / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D010778:Photochemotherapy; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D016227:Benzoquinones; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D042442:Vascular Endothelial Growth Factors; C112765:tanespimycin; D020782:Matrix Metalloproteinases