Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance

Abstract

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of oncogenesis that are associated with all hallmarks of cancer. Accumulating evidence has demonstrated that the client proteins are guided for proteasomal degradation when their complexes with HSP90 are disrupted. Accordingly, HSP90 and its co-chaperones have emerged as viable targets for the development of cancer therapeutics. Consequently, a number of natural products and their analogs targeting HSP90 have been identified. They have shown a strong inhibitory effect on various cancer types through different mechanisms. The inhibitors act by directly binding to either HSP90 or its co-chaperones/client proteins. Several HSP90 inhibitors—such as geldanamycin and its derivatives, gamitrinib and shepherdin—are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics.

Isolation of lymph shows dysregulation of STAT3 and CREB pathways in the spleen and liver during leukemia development in a rat model

“…The cytoplasmatic HSP90 alpha and beta‐isoforms are upregulated in various types of cancer and HSP‐90 together with its co‐chaperones seem to play an important role in metastatic behavior 17,18 . HSP‐90 inhibitors such as geldanamycin are under clinical trials as cancer therapeutics with promising results 18 . Leukotriene A‐4 hydrolase is an important regulator of inflammation and is overexpressed in many types of cancer cells.…”

Gkongensin A, an HSP90β inhibitor, improves hyperlipidemia, hepatic steatosis, and insulin resistance

“…It is urgent for us to find new drug treatments and drug targets in conflict with obesity and pertinent metabolic disorders. In the last ten years, HSP90 has become a major therapeutic target for cancer [ 23 ], neurodegenerative disorders [ 24 ], anti-viral [ 25 ], and anti -osteoclastogenesis [ 26 ]. Although there are promising opportunities in utilizing HSP90 inhibitors for treating illnesses, the role of four paralogs from the HSP90 chaperone family in diseases is still not well comprehended.…”

HSP90 expression is associated with outcome in pulmonary carcinoid tumor patients

“…Recently, several studies have shown with neuroendocrine cell lines, xenograft models and patient-derived SI-NET tumor cells that inhibitors of HSP90 can potentiate the tumor cell killing effect of radiotherapy ( 18 , 19 , 25 , 26 ). Indeed, several HSP90-targeted drugs have been reported and studied in preclinical and clinical models ( 23 , 27 ). However, none of these HSP90 inhibitors are in clinical use for the treatment of any cancer type due to dose-limited toxicity, drug resistance and poor bioavailability.…”