Biological Evaluation of 3-Acyl-2-Arylamino-1,4-Naphthoquinones as Inhibitors of Hsp90 Chaperoning Function

David      Rios; Julio      Benites; Jaime   A.   Valderrama; Mirelle      Farias; Rozangela   C.   Pedrosa; Julien      Verrax; Pedro   Buc   Calderon

doi:10.2174/1568026611212190007

Abstract

Hsp90 is a chaperone that plays a key function in cancer cells by stabilizing proteins responsible of cell growth and survival. Disruption of the Hsp90 chaperone machinery leads to the proteasomal degradation of its client proteins. Hsp90 appears then as an attractive target for the development of new anticancer molecules. We have shown that ascorbate- driven menadione-redox cycling inhibits Hsp90 activity by provoking an N-terminal cleavage of the protein, inducing the degradation of several of its client proteins. Since the mechanism involves an oxidative stress, we explored the effect of a series of diverse donor-acceptor 3-acyl-2-phenylamino 1,4-naphthoquinones on Hsp90 integrity, in the presence of ascorbate. Results show that quinone-derivatives that bear two electroactive groups (namely quinone and nitro) exhibit the highest inhibitory activity (Hsp90 cleavage and cell death). The biological activity of the series mainly relies on their redox capacity and their lipophilicity, which both modulate the ability of these compounds to induce a cytotoxic effect in K562 cells. As observed with other redox cycling quinones, the protein cleavage is blocked in the presence of N-terminal Hsp90 inhibitors suggesting that the availability or occupancy of nucleotide binding site in the N-terminal pocket of Hsp90 plays a critical role. In addition the survival of cancer cells and their metabolic and redox homeostasis were strongly impaired by the presence of ascorbate. Since these effects were similar to that obtained by ascorbate/menadione and they were blocked by the antioxidant N-acetylcyteine (NAC), it appears that oxidative stress is a major component of this cytotoxicity.

Keywords: Cancer cell death, Hsp90, oxidative stress, protein cleavage, quinones, redox cycling, lipophilicity, cancer cells, N-acetylcyteine (NAC), cytotoxic, client proteins.