Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules

Seong-Hyun Park,Sang-Hyun Park,Won-Je Kim,Hui Li,Hwan Kim,Sang Chul Shin,Taebo Sim,Wonil Seo,Injae Shin,Nak-Kyoon Kim,Erik R P Zuiderweg,Eunice Eunkyeong Kim

doi:10.1038/s41598-017-03814-6

Abstract

In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an ATPase domain of Hsc70 and thus blocks ATP binding to the protein. Observations made in the cell study indicated that Az treatment promotes leukemia cell death by activating caspase-dependent apoptosis without affecting the caspase-independent apoptotic pathway. Importantly, the hybrids composed of Az and geldanamycin, which have high inhibitory activities towards both Hsp70 and Hsp90, exhibit enhanced anti-leukemia activity relative to the individual inhibitors. However, the Az and imatinib hybrids have weak inhibitory activities towards Hsp70 and Abl, and display lower cytotoxicity against leukemia cells compared to those of the individual constituents. The results of a mechanistic study showed that the active hybrid molecules promote leukemia cell death through a caspase-dependent apoptotic pathway. Taken together, the findings suggest that Hsp70 inhibitors as well as their hybrids can serve as potential anti-leukemia agents.

Highlights

In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp[70] proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp[90] or Abl kinase
The results of previous investigations indicate that inhibition of Hsp[90] in itself is insufficient to bring about cancer cell death because exposure to geldanamycin or its synthetic derivatives induces upregulation of Hsp7020
Saturation transfer difference (STD) NMR studies were conducted initially to obtain information on Az binding to the ATPase domain of Hsc7030

Summary

Introduction

In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp[70] proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp[90] (geldanamycin) or Abl kinase (imatinib). Hsp[70] proteins are potent targets for cancer diagnosis and prognosis, and their inhibitors are potential chemotherapeutic agents for treatment of various cancers[12, 13] Another class of ATP-dependent molecular chaperone, Hsp[90], is known to bind and stabilize various cancer-associated client proteins, including Bcr-Abl[14, 15]. The results of previous investigations indicate that inhibition of Hsp[90] in itself is insufficient to bring about cancer cell death because exposure to geldanamycin or its synthetic derivatives induces upregulation of Hsp7020. This upregulation leads to a decrease in the anticancer activities of Hsp[90] inhibitors. Inhibition of Hsp[90] and Hsp[70] proteins should be an important therapeutic strategy to generate efficacious anticancer agents[21, 22]

Methods

Results

Conclusion