HSP90 and its inhibitors (Review)

Huang, Hao; Naomoto, Yoshio; Bao, Xiaohong; Watanabe, Nobuyuki; Sakurama, Kazufumi; Noma, Kazuhiro; Motoki, Takayuki; Tomono, Yasuko; Fukazawa, Takuya; Shirakawa, Yasuhiro; Yamatsuji, Tomoki; Matsuoka, Junji; Takaoka, Munenori

doi:10.3892/or_00000787

Cited by 6 publications

(1 citation statement)

References 117 publications

(153 reference statements)

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“…The methoxy substituent of benzoquinone moiety in geldanamycin was replaced by an allyloamine group (17-AAG; tanespimycin), dimethyl-aminoethylamine group (17-DMAG; alvespimycin) or changed for an amine group (17-AG, IPI-493) [81]. Moreover, 17-AAG hydrochloride (IPI-504) was obtained by a reduction of benzoquinone moiety in 17-AAG to hydrochinon [85].…”

Section: Benzoquinone Inhibitorsmentioning

confidence: 99%

Inhibitors of HSP90 in melanoma

Mielczarek-Lewandowska

Hartman

Czyż

2019

Apoptosis

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HSP90 (heat shock protein 90) is an ATP-dependent molecular chaperone involved in a proper folding and maturation of hundreds of proteins. HSP90 is abundantly expressed in cancer, including melanoma. HSP90 client proteins are the key oncoproteins of several signaling pathways controlling melanoma development, progression and response to therapy. A number of natural and synthetic compounds of different chemical structures and binding sites within HSP90 have been identified as selective HSP90 inhibitors. The majority of HSP90-targeting agents affect N-terminal ATPase activity of HSP90. In contrast to N-terminal inhibitors, agents interacting with the middle and C-terminal domains of HSP90 do not induce HSP70dependent cytoprotective response. Several inhibitors of HSP90 were tested against melanoma in pre-clinical studies and clinical trials, providing evidence that these agents can be considered either as single or complementary therapeutic strategy. This review summarizes current knowledge on the role of HSP90 protein in cancer with focus on melanoma, and provides an overview of structurally different HSP90 inhibitors that are considered as potential therapeutics for melanoma treatment.

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Section: Benzoquinone Inhibitorsmentioning

confidence: 99%

Inhibitors of HSP90 in melanoma

Mielczarek-Lewandowska

Hartman

Czyż

2019

Apoptosis

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Characterization and expression analysis of heat shock proteins HfHspc1 and HfHspc4 in Haemaphysalis flava ticks

Li,

Wang,

Feng

et al. 2024

Parasitol Res

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Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer

Liu

Hua

et al. 2015

Cell Death Dis

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Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR. Cell Death and Disease (2015) 6, e1595; doi:10.1038/cddis.2014.555; published online 15 January 2015Gastric cancer (GC) remains the fifth most common cancer worldwide, with an estimated 9 52 000 new cases (7% of total cancer incidence) and 7 23 000 deaths (9% of total cancer mortality) in 2012. 1 As a highly aggressive and lethal malignancy, the aggressive nature of GC is linked to mutations in tumor suppressor genes, oncogenes, growth factors and their receptors, and so on. 2 Till now, there are few effective treatment options for advanced patients with distant metastasis or recurrence. 3 The detailed mechanisms that regulate GC are not yet fully understood; therefore, such situations underscore the persistent unmet need to identify therapeutics that target pa...

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HSP90 and its inhibitors (Review)

Cited by 6 publications

References 117 publications

Inhibitors of HSP90 in melanoma

Inhibitors of HSP90 in melanoma

Characterization and expression analysis of heat shock proteins HfHspc1 and HfHspc4 in Haemaphysalis flava ticks

Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer

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