Inhibition of Hsp90: a new strategy for inhibiting protein kinases

Sreedhar, Amere Subbarao; Sőti, Csaba; Csermely, Péter

doi:10.1016/j.bbapap.2003.11.027

Cited by 141 publications

(88 citation statements)

References 110 publications

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“…The small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is a geldanamycin analogue that inhibits HSP90 function (4,13,15). Both geldanamycin and 17-AAG have been shown to induce cell cycle arrest and apoptosis in a variety of tumor types (5).…”

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confidence: 99%

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Georgakis¹,

Yang²,

Rassidakis

et al. 2006

Clinical Cancer Research

114

100

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Purpose: Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma. Experimental Design: HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot. Results: HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time-and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines.17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal^regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti^tumor necrosis factor^related apoptosisinducing ligand (TRAIL) death receptor antibodies. Conclusion: Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti^tumor necrosis factor^related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.

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confidence: 99%

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Georgakis¹,

Yang²,

Rassidakis

et al. 2006

Clinical Cancer Research

114

100

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“…Among several anticancer drugs that are under clinical evaluation, Hsp90 inhibitor drug 17AAG [23][24] and antioxidant and anti-inflammatory drug curcumin [6] are attributed for their selectivity and specificity against a large variety of cancer cells. Considering the growing interest and beneficial effects of combinatorial drug treatments in treating cancer, we have examined for combinatorial effects of 17AAG and curcumin against human neuroblastoma tumor cells.…”

Section: Discussionmentioning

confidence: 99%

17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line

Taiyab¹,

Usha²,

Amere³

2010

JCT

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Pharmacological inhibition of Hsp90 has emerged as a novel anticancer treatment. In this study we have investigated the effect of Hsp90 inhibitor drug 17AAG combination with curcumin on human neuroblastoma cells. The 17AAG treatment of cells for 18 h induced G1/S cell cycle arrest associated with cyclin D1 down regulation, and degradation of Raf-1 and inactivation of Akt. However, 17AAG treatment activated the mitogen kinase, ERK1, and induced the expression of stress proteins, Hsp70 and p53. The curcumin treatment resulted in G2/M cell cycle arrest and activation of both Raf1 and ERK1 kinases. The drugs in combination induced proteolytic degradation of Raf1 and Akt, and surpassed curcumin induced G2/M arrest. The combination treatment additionally inactivated MEK, inhibited activation and nuclear localization of ERK1, and also inhibited the stress protein induction. EGF stimulation induced re-activation of mitogen signaling with individual drug treatments but not in combination.This study highlights that 17AAG combination with curcumin selectively targets mitogen signal transduction mechanism through ERK1 inactivation. In conclusion, our study proposes the beneficial effects of 17AAG combination with curcumin in combating cancer.

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“…After analyzing the cancer kinome, oncogenic signaling pathways including cell cycle dependent kinases (cdks) are identified as signatures of cancer [13]. Following that Hsp90 is identified as the major chaperone involved in the functions of several oncogenic kinases including cdks, pharmacological targeting of Hsp90 has emerged as a novel antitumor strategy [14,15]. Since mitotic kinases play significant role in cancer progression, Hsp90 involvement in mitotic control through checkpoint kinases require further studies.…”

Section: Introductionmentioning

confidence: 99%

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

Vinay¹,

Reddy²,

Kumar³

et al. 2013

JCT

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Mitosis-targeted anti-cancer therapies gained much attention in recent years. However, lack of tumor selectivity poses limitations to the current anti-mitotic drugs to be used as broad-spectrum anti-cancer agents. In this study, we show that combination treatment of colcemid, an inhibitor of microtubule polymerization with geldanamycin, an inhibitor of cancer chaperone, Hsp90 irreversibly targets mitosis through mitotic kinase bubR1 stabilization. When the individual and combination drugs treatments were tested against tumor cells (IMR-32 and HeLa) and non-tumor cells (SRA01), the combination treatment showed significant increase in cytotoxicity only in tumor cells followed by G2/M cell cycle block. The IMR-32 cells showed enhanced cytotoxicity in response to combination treatments, compared to HeLa cells. Further studies revealed that the G2/M arrest in IMR-32 correlates with both increased bubR1 nuclear localization and metaphase arrest. The siRNA knockdown of bubR1 has decreased tumor cell response to geldanamycin suggesting Hsp90-dependent regulation of bubR1. The combination treatment also showed inactivation of non-canonical β-catenin signaling suggesting inhibition of cancer growth. In addition, the combination treatment has significantly affected the distribution and functions of bubR1 downstream mitotic kinases such as aurks and plk1 indicating the combinatorial attack of combination treatment. In conclusion, we demonstrate that colcemid and GA combination treatment compromises the division potential of tumor cells interfering with the mitosis through bubR1 kinase.

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Inhibition of Hsp90: a new strategy for inhibiting protein kinases

Cited by 141 publications

References 110 publications

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

Inhibition of Heat Shock Protein 90 Function by 17-Allylamino-17-Demethoxy-Geldanamycin in Hodgkin's Lymphoma Cells Down-Regulates Akt Kinase, Dephosphorylates Extracellular Signal–Regulated Kinase, and Induces Cell Cycle Arrest and Cell Death

17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line

Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells

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