Effects of Hsp90 inhibition in neuroblastoma: analysis of drug sensitivity, target modulation and the influence of bone marrow microenvironment.
Heat shock protein 90 (Hsp90) safeguards the structural integrity and function of many of the key growth regulatory proteins found in malignant cells. Consequently, among the new generation targeted therapeutics, heat shock protein inhibitors have the unique property of being able to target an expansive array of divergent molecular mechanisms involved in cancer growth and metastasis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) is one such agent that has been shown to bind to Hsp90 and thus reduce the stability and activity of many key growth regulatory molecules and pathways. A number of recent clinical trials have investigated the maximum tolerated dose, toxicity and pharmacokinetic profiles of 17-AAG in pediatric patients with recurrent tumors. In this study, we describe the effects of 17-AAG against a panel of neuroblastoma (NB) cell lines with respect to cytotoxicity, target modulation and inhibition of vascular endothelial growth factor (VEGF) expression. 17-AAG was found to inhibit the growth of all NB cell lines tested, though effective inhibitory concentrations varied among cell lines. 17-AAG also suppressed the expression of VEGF. The cytotoxic effect of 17-AAG on tumor cells was diminished when co-cultured with bone marrow stromal cells suggesting a potential role for the microenvironment in tumor drug interactions. Findings from target modulation analysis as well as drug combination assays provide a frame-work to formulate effective protocols for the treatment of NB.
Jayanthan
Aarthi
A
Translational Research Laboratories, Tom Baker Cancer Centre and the Division of Pediatric Oncology Alberta Children's Hospital, Calgary, Alberta, Canada.
Fowler
Jane
J
Hawkins
Lindsay
L
Lamers
Fieke
F
Teja
Bijan
B
Incoronato
Andrea
A
Anderson
Ronald
R
Narendran
Aru
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004351:Drug Resistance / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D020714:Maximum Tolerated Dose; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C112765:tanespimycin