Hsp90-inhibitor geldanamycin abrogates G2 arrest in p53-negative leukemia cell lines through the depletion of Chk1

Sugimoto, Koichi; Sasaki, Makoto; Isobe, Yasushi; Tsutsui, Miyuki; Suto, Hiroko; Ando, Jun; Tamayose, Kenji; Oshimi, Kazuo

doi:10.1038/sj.onc.1210978

Cited by 24 publications

(26 citation statements)

References 38 publications

(44 reference statements)

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“…Previous reports demonstrated that HSP90 inhibitors can sensitize cells to the cytotoxic effects of DNAdamaging agents, including IR, primarily through downregulation of cell survival and cytoprotective factors (Arlander et al, 2003;Bisht et al, 2003;Rahmani et al, 2003;Bull et al, 2004;Dote et al, 2006;Robles et al, 2006). However, GA has also been shown to abrogate G 2 arrest in doxorubicin-treated lymphoma and irradiated carcinoma cells (Bull et al, 2004;Dote et al, 2006;Robles et al, 2006;Sugimoto et al, 2007). Mechanistic studies on the enhancement of IR cytotoxicity by HSP90 inhibition, particularly those focusing on G 2 checkpoint abrogation, are limited.…”

Section: Introductionmentioning

confidence: 99%

Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells

et al. 2008

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Section: Introductionmentioning

confidence: 99%

Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells

et al. 2008

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“…Compounds that target other components of the ATR pathway are few in number and typically affect nonspecific processes such as protein chaperones and stability. For example, Hsp90 inhibitors (geldanamycin and 17-allylamino-17-demethoxygeldanamycin (17-AAG)) deplete Chk1 and hence block ATR pathway function, as well as many other targets (18,19). …”

Section: Introductionmentioning

confidence: 99%

Identification of ATR–Chk1 Pathway Inhibitors That Selectively Target p53-Deficient Cells without Directly Suppressing ATR Catalytic Activity

et al. 2014

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Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells where the G1/S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2/M checkpoints mediated by the ATR and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1. To discover small molecules that may act on uncharacterized components of the ATR pathway, we performed a phenotype-based screen of 9,195 compounds for their ability to inhibit hydroxyurea-induced phosphorylation of Ser345 on Chk1, known to be a critical ATR substrate. This effort led to the identification of four small-molecule compounds, three of which were derived from known bioactive library (anthothecol, dihydrocelastryl, and erysolin) and one of which was a novel synthetic compound termed MARPIN. These compounds all inhibited ATR-selective phosphorylation and sensitized p53-deficient cancer cells to DNA-damaging agents in vitro and in vivo. Notably, these compounds did not inhibit ATR catalytic activity in vitro, unlike typical ATP-competitive inhibitors, but acted in a mechanistically distinct manner to disable ATR-Chk1 function. Our results highlight a set of novel molecular probes to further elucidate druggable mechanisms to improve cancer therapeutic responses produced by DNA-damaging drugs.

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“…As Hsp90 expression is particularly high in cancer cells and is associated with tumor cell progression, invasion and formation of metastases, as well as development of drug resistance [2], geldanamycin and its analogues have been considered for treament of cancer [2,3,12,15,16,17,18,19]. Geldanamycin has been shown to induce apoptosis [1,5,6,8,9,10,15,20,21,22,23], an effect paralleled by altered gene expression, downregulation of Akt, p38 MAPK activation, mitochondrial depolarization, reactive oxygen species formation, decline of reduced glutathion, lipid peroxidation and caspase activation [5,9,15,20,21]. On the other hand, geldanamycin may counteract neuronal injury, an effect attributed to destabilization of RIP1 protein [4,7,24].…”

Section: Introductionmentioning

confidence: 99%

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

Jilani

Qadri

Läng

2013

Cell Physiol Biochem

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Background/aims: Geldanamycin, a benzoquinone ansamycin antibiotic, and its analogues induce apoptosis of tumor cells and are thus considered for the treatment of cancer. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-concentration ([Ca²⁺]_i) and formation of ceramide. The present study explored, whether geldanamycin modifies [Ca²⁺]_i, ceramide formation, cell volume and phosphatidylserine abundance at the erythrocyte surface. Methods: Erythrocyte volume was estimated from forward scatter, phosphatidylserine-abundance from annexin V binding, hemolysis from hemoglobin release, ceramide formation from binding of fluorescent antibodies and [Ca²⁺]_i from Fluo3-fluorescence. Results: A 48 hours exposure to geldanamycin significantly decreased forward scatter (≥ 5 µM), significantly increased annexin-V-binding (≥ 25 µM), but did not significantly modify Fluo3-fluorescence (up to 50 µM). The annexin-V-binding following geldanamycin treatment was not significantly modified by removal of extracellular Ca²⁺ but was paralleled by significantly increased ceramide formation (50 µM). Conclusions: Geldanamycin stinulated eryptosis, an effect at least partially due to ceramide formation.

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Hsp90-inhibitor geldanamycin abrogates G2 arrest in p53-negative leukemia cell lines through the depletion of Chk1

Cited by 24 publications

References 38 publications

Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells

Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells

Identification of ATR–Chk1 Pathway Inhibitors That Selectively Target p53-Deficient Cells without Directly Suppressing ATR Catalytic Activity

Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane

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