High cytotoxic sensitivity of the oligodendrocyte precursor cells to HSP90 inhibitors in cell cultures.
Oligodendrocyte precursor cells (OPCs) are able to proliferate, and most differentiate into post-mitotic oligodendrocytes that contribute to remyelination. We have previously studied the expression of heat shock protein90 (HSP90) in OPCs. The ansamycins, such as geldanamycin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) act as specific HSP90 inhibitors, are potent anti-tumor agents and are currently undergoing clinical trials. This work investigated the effect of HSP90 inhibitors on cultured OPCs. Geldanamycin, 17-AAG and another chemically unrelated HSP90 inhibitor, radicicol, were extremely cytotoxic for OPCs. The IC50 values of geldanamycin, 17-AAG and radicicol for OPCs were 7.1, 10.7 and 137 nM, respectively, compared to 1000-2000 nM for preoligodendrocytes, astrocytes and neurons. Adult OPCs were found to be susceptible to HSP90 inhibitors in a similar fashion to perinatal cells. OPC death induced by these HSP90 inhibitors led to a significant decrease in the oligodendrocyte population. The present results highlight that OPCs are uniquely sensitive to HSP90 inhibitors. Geldanamycin and 17-AAG, which penetrate the blood-brain barrier, are novel cancer chemotherapeutic agents and we noted that, in anti-cancer therapy with these drugs, the OPCs may be compromised.
Alcazar
Alberto
A
Department of Investigation, Hospital Ramón y Cajal, Ctra. Colmenar km 9.1, E-28034, Madrid, Spain. alberto.alcazar@hrc.es
Cid
Cristina
C
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D019081:O Antigens / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D051381:Rats; D013234:Stem Cells; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin / Q000378:metabolism
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D019081:O Antigens; D013778:Tetrazolium Salts; D013844:Thiazoles; C488416:Tubb3 protein, rat; D014404:Tubulin; C062875:ganglioside A2B5; C112765:tanespimycin; C022616:thiazolyl blue; C035359:monorden; C001277:geldanamycin