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.