Heat-Shock Protein 90 Inhibitors: Will They Ever Succeed as Chemotherapeutics?

Wang, Yao; McAlpine, Shelli R.

doi:10.4155/fmc.14.154

Cited by 24 publications

(31 citation statements)

References 20 publications

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“…Using this method, we demonstrated that CDDO-Me interacts with Hsp90 in cells. This was further supported by the induction of Hsp70, a universe response observed in cells upon treated with Hsp90 inhibitors, especially those targeting the N-terminus of Hsp90 [ 30 ]. Moreover, the client proteins of Hsp90, such as ErbB2 and Akt, could also be reduced by CDDO-Me treatment.…”

Section: Discussionmentioning

confidence: 99%

Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

et al. 2015

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Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt), indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significantly inhibits cell proliferation and enhances the anti-proliferation effect of CDDO-Me in H08910 ovarian cancer cells. Dithiothreitol inhibits the interaction of CDDO-Me with Hsp90 in cells and abrogates CDDO-Me induced upregulation of Hsp70, degradation of Akt and cell proliferation inhibition. This suggests the anti-ovarian cancer effect of CDDO-Me is possibly mediated by the formation of Michael adducts between CDDO-Me and reactive nucleophiles on Hsp90. This study identifies Hsp90 as a novel target protein of CDDO-Me, and provides a novel insight into the mechanism of action of CDDO-Me in ovarian cancer cells.

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Section: Discussionmentioning

confidence: 99%

Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

et al. 2015

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“…[12][13][14][15]17,28 Specifically, the SM series of compounds, whose most effective molecule, SM258, completely depletes the HSF1 protein in drug-treated cells via allosteric modulation of Hsp90's C-terminus (Fig. 3b).…”

Section: Introductionmentioning

confidence: 98%

“…3a). [12][13][14][15][16]28,54 The induction of the HSR and elevated HSF1 promotes resistance. The classic Hsp90 inhibitors has been known to cause the HSR and increased HSF1 levels for the last 2 decades, however, the recent developments in the understanding of HSF1 and its integral part in cancer initiation highlights the need for other types of Hsp90 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…The role of Hsp90, 70, 40, and 27 in cancer cell growth is reasonably well described in the recent literature. [12][13][14][15][16][17][18][19][20][21] However, it is often overlooked that HSF1 contributes to the malignant phenotype though mechanisms distinct from the HSR. In cancer cells more than 60% of the DNA elements bound by HSF1 are unique from those driven by heat shock.…”

Section: Introductionmentioning

confidence: 99%

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Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach

McConnell

Buckton

McAlpine

2015

Bioorganic & Medicinal Chemistry Letters

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“…Most of the well-known Hsp90 inhibitors target N-terminal of Hsp90 and block the binding of adenosine triphosphate molecules. In this event, a heat-shock response can be produced, followed by induction of Hsp70 [41,42]. This protein plays a role in the antiapoptotic pathway, and it can reduce the efficiency of tumor cell killing by Hsp90 inhibitors.…”

Section: Other Radiosensitizers To Target Multiple Signaling Pathwaysmentioning

confidence: 99%

Strategies to Enhance Radiosensitivity to Heavy Ion Radiation Therapy

Lee

Okayasu

2018

International Journal of Particle Therapy

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Heavy ion radiation therapy has been increasingly used due to several advantages over low linear energy transfer (LET) photon therapy, but further improvement of its therapeutic efficacy would be necessary. In this review, we summarize effective radiosensitizers for heavy ion radiation therapy and mechanisms associated with the radiosensitization. High LET heavy ions induce more complex and clustered DNA damage than low LET radiation. Inhibition of homologous recombimation repair or nonhomologous end rejoining and dysfunctional cell cycle checkpoint have been reported to sensitize cancer cells to heavy ions. Radiosenstizing agents, including DNA damage response inhibitors, Hsp90 inhibitors, histone acetylase inhibitors, and nanomaterials have been found to enhance cell killing by heavy ion irradiation through disrupted DNA damage response, cell cycle arrest, or other cellular processes. The use of these radiosensitizers could be a promising strategy to enhance the efficacy of heavy ion radiation therapy.

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Heat-Shock Protein 90 Inhibitors: Will They Ever Succeed as Chemotherapeutics?

Cited by 24 publications

References 20 publications

Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach

Strategies to Enhance Radiosensitivity to Heavy Ion Radiation Therapy

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