Co-treatment with heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and vorinostat: a highly active combination against human Mantle Cell Lymphoma (MCL) cells

Abstract

Heat shock protein (hsp) 90 inhibitors promote proteasomal degradation of pro-growth and pro-

survival hsp90 client proteins, including CDK4, c-RAF and AKT, and induce apoptosis of

human lymphoma cells. The pan-histone deacetylase inhibitor vorinostat has also been shown to

induce growth arrest and apoptosis of lymphoma cells. Here, we determined the effects of the

more soluble, orally bio-available, geldanamycin analogue 17-NN-dimethyl ethylenediamine

geldanamycin (DMAG, Kosan Biosciences Inc) and/or vorinostat in cultured and primary human

MCL cells. While vorinostat induced accumulation in the G1 phase, treatment with DMAG

arrested MCL cells in the G2/M phase of the cell cycle. Both agents dose-dependently induced

apoptosis of MCL cells. Vorinostat also induced hyperacetylation of hsp90 and disrupted the

association of hsp90 with its co-chaperones p23 and cdc37, as well as with its client proteins

CDK4 and c-RAF. Treatment of MCL cells with vorinostat or 17-DMAG was associated with

the induction of p21 and p27, as well as with depletion of c-Myc, c-RAF, AKT and CDK4.

Compared to treatment with either agent alone, co-treatment with DMAG and vorinostat

markedly attenuated the levels of cyclin D1 and CDK4, as well as of c-Myc, c-RAF and AKT.

Combined treatment with DMAG and vorinostat synergistically induced apoptosis of the

cultured MCL cells, as well as induced more apoptosis of primary MCL cells than either agent

alone. Therefore, these findings support the rationale to determine the in vivo efficacy of co-

treatment with vorinostat and DMAG against human MCL cells.