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Abstract
Heat shock protein 90 (Hsp90) is a conserved and constitutively expressed molecular chaperone and it has been shown to stabilize oncoproteins and facilitate cancer development. Hsp90 has been considered as a therapeutic target for cancers and three classes of Hsp90 inhibitors have been developed: (1) benzoquinone ansamycin and its derivatives, (2) radicicol and its derivates, and (3) small synthetic inhibitors. The roles of these inhibitors in cancer treatment have been studied in laboratories and clinical trials, and some encouraging results have been obtained. Interestingly, targeting of Hsp90 has been shown to be effective in inhibition of cancer stem cells responsible for leukemia initiation and progression, providing a strategy for finding a cure. Because cancer stem cells are well defined in some human leukemias, we will focus on hematologic malignancies in this review.
Highlights
Heat Shock Protein 90 (Hsp90) is a highly conserved, constitutively expressed molecular chaperone that facilitates folding of its client proteins that are involved in signal transduction, protein trafficking, receptor maturation and innate and adaptive immunity [1]
It has been shown that cancer cells use the Hsp90 chaperone machinery to facilitate the function of numerous oncoproteins; Hsp90 is considered as an important therapeutic target in cancers, which has led to the development of Hsp90 inhibitors
Hsp90 inhibitors are a diverse group of novel agents that have been demonstrated to have pro-apoptotic effects on malignant cells through inhibition of adenosine triphosphate (ATP) binding in the ATP/ADP-binding pocket of the heat shock protein
Summary
Heat Shock Protein 90 (Hsp90) is a highly conserved, constitutively expressed molecular chaperone that facilitates folding of its client proteins that are involved in signal transduction, protein trafficking, receptor maturation and innate and adaptive immunity [1]. Pharmaceuticals 2012, 5 generated in a complex cycle of adenosine triphosphate (ATP) binding and hydrolysis to assist protein folding. In these processes, client proteins recognition by Hsp is guided by co-chaperones, such as cell division cycle 37 (CDC37) and cyclin-dependent kinase inhibitor p23 [2]. Progress in the preclinical and clinical evaluation of Hsp inhibitors in hematological malignancies has demonstrated the important role of Hsp in cancer development. This review describes recent advances in our understanding of Hsp biology and its inhibitors for the treatment of cancers, especially hematological malignancies and leukemia stem cells (LSCs)
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