High anti tumor activity against rhabdomyosarcoma cells and low normal cells cytotoxicity of heat shock protein 90 inhibitors, with special emphasis on 17-[2-(pyrrolidin-1-yl)ethyl]-aminno-17-demethoxygeldanamycin.
Rhabdomyosarcoma is a highly metastatic tumor, mostly observed in children and adolescence. When diagnosed at early stages it is mostly curable. However, in advanced or metastatic stages the 5-years survival rate is below 20%. Thus, new treatment strategies for this tumor are needed. In this paper we showed that HSP90 inhibitors, geldanamycin and its analogs, can profoundly affect proliferation of rhabdomyosarcoma cells. We also showed that blocking of HSP90 function induces apoptosis of tumor cells and downregulates expression of anti apoptotic protein AKT. Cells exposed to geldanamycin and its analogs exhibit strong reduction of MET receptor expression and subsequent inhibition of HGF-dependent tumor cells migration and invasion. Interestingly, at concentrations sufficient to block tumor cells growth and motility, the 17AEP-GA, 17AAG and 17DMAP-GA were not toxic or only slightly toxic toward normal hematopoietic, mesenchymal and endothelial cells. This could be due to low HSP90 expression both at mRNA and protein level in these cells. Collectively, our findings suggest that blocking HSP90 action through geldanmycins could be in the future a part of new therapeutic strategies in rhabdomyosarcoma treatment.
Lukasiewicz
E
E
Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University School of Medicine, Cracow, Poland.
Miekus
K
K
Kijowski
J
J
Gozdzik
J
J
Wilusz
M
M
Bobis-Wozowicz
S
S
Wiecha
O
O
Majka
M
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C548185:17-(2-(pyrrolidin-1-yl)ethyl)-amino-17-demethoxygeldanamycin; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C001277:geldanamycin