A Radicicol Derivative, KF58333, Inhibits Expression of Hypoxia‐inducible Factor‐1α and Vascular Endothelial Growth Factor, Angiogenesis and Growth of Human Breast Cancer Xenografts

Kurebayashi, Junichi; Otsuki, Takemi; Kurosumi, Masafumi; Soga, Shiro; Akinaga, Shiro; Sonoo, Hiroshi

doi:10.1111/j.1349-7006.2001.tb02159.x

Cited by 56 publications

(31 citation statements)

References 29 publications

(45 reference statements)

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“…Furthermore, Hsp90 inhibitors have already exhibited promising antitumor activity such as antiproliferative and antiangiogenic effects (Oikawa et al, 1993;Neckers et al, 1999). Another Hsp90 inhibitor, the oxime derivative of radicicol known as KF58333 (1 M), decreased the HIF-1␣ protein level under both normoxia and hypoxia in human breast cancer cells in vitro and inhibited growth and angiogenesis in human breast cancer xenografts (Kurebayashi et al, 2001). Therefore, Hsp90 inhibitors could become useful as hypoxia-sensitive and therapeutic antiangiogenic and antitumor agents.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol

et al. 2002

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Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the ␣ subunit of hypoxia-inducible factor-1 (HIF-1␣), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1␣/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 g/ml) does not significantly change the stability of the HIF-1␣ protein and does not inhibit the nuclear localization of HIF-1␣. However, this dose of radicicol significantly reduces HRE binding by the HIF-1␣/Arnt heterodimer. Our results, the first to show that radicicol specifically inhibits the interaction between the HIF-1␣/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1␣/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.Cells adapt to hypoxia by up-regulating the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Pathologically, tumor hypoxia contributes directly to enhanced glucose metabolism and angiogenesis, which are major features of malignant progression. The genes up-regulated during hypoxia include vascular endothelial growth factor (VEGF), erythropoietin, and several glycolytic enzymes. These diverse, targeted genes are induced by a common trans-activator, hypoxia-inducible factor 1 (HIF-1) (Iyer et al., 1998;Bruick and McKnight, 2001b;Semenza, 2002).HIF-1 was first identified as a heterodimeric trans-activator composed of two subunits, HIF-1␣ and -␤, both of which belong to the growing family of basic-helix-loop-helix-PAS (bHLH-PAS) proteins, including period (Per), Arnt, and single-minded (Sim). The bHLH-PAS proteins share common characteristics: first, a bHLH-PAS protein dimerizes with a specific partner protein through the HLH-PAS domain. Second, a partner such as the aryl hydrocarbon receptor (AhR) or HIF-1␣ is activated by specific stimuli (i.e., xenobiotics or low oxygen tension, respectively) before translocating to the nucleus, where it heterodimerizes with a partner protein. Alternatively, Arnt, another bHLH-PAS protein, is constitutively located in the nucleus and interacts with several

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Section: Discussionmentioning

confidence: 99%

Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol

et al. 2002

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“…Geldanamycin induces degradation of HIF-1α in prostate cancer cells and a radicicol derivative (KF58333) inhibited expression of HIF-1α and VEGF and reduces vascularisation and growth of breast carcinoma xenografts (Kurebayashi 2001) Tumours grown in mice with deficient angiogenesis (id-/-mice) are more sensitive to 17AAG compared with those in wild type mice (Candia 2003). Therefore 'classical' angiogenesis inhibitors in combination with inhibitors of Hsp90 function may be useful in anticancer therapy.…”

Section: Molecular Chaperone Hsp90mentioning

confidence: 99%

Parallels in invasion and angiogenesis provide pivotal points for therapeutic intervention

Eccles¹

2004

Int. J. Dev. Biol.

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Biological evolution is economical and successful fundamental processes are frequently recapitulated. There are remarkable similarities in the molecular mechanisms which enable tumour cells to invade into surrounding tissues and activated endothelial cells to generate new capillaries, which facilitate the growth and dissemination of cancer. Indeed these pathological processes are themselves based upon key vertebrate developmental processes, and in some cases parallel strategies used by microorganisms to colonise their hosts' tissues. The aim of this review is to explore these parallels in more detail and indicate possible pivotal points for therapeutic intervention. These novel approaches may ultimately optimise the selective targeting of processes involved in tumour invasion and angiogenesis, while sparing normal adult proliferating tissues. Strategies include inhibition of oncogenic pathways in tumour cells which not only stimulate tumour cell growth and invasion, but also initiate neoangiogenesis by upregulation of angiogenic cytokines. Secondly, downstream signalling pathways, transcriptional regulation and effectors common to both processes, and finally points of interaction/cross-talk between tumour cells and endothelial cells which are necessary to enable invasion and angiogenesis to proceed. +44-20-8722-4134. e-mail: sue.eccles@icr.ac.uk Abbreviations used in this paper: ADAM, adamalysin related membrane protease; APC, adenomatous polyposis coli; BM, basement membrane; BTC, betacellulin; COX-2, cyclo-oxygenase 2; FAK, focal adhesion kinase; FAP, familial adenomatous polyposis; FGF(R), fibroblast growth factor (receptor); GSK3, glycogen synthase kinase 3; HGF, hepatocyte growth factor; HIF, hypoxia inducible factor; HRG, heregulin; IL, interleukin; ILK, integrin linked kinase; iNOS, inducible nitric oxide synthase; MAPK, mitogen activated kinase; MIF, migration inhibitory factor; MMP, matrix metalloprotease; NSAID, non-steroidal anti-inflammatory drug; OPN, osteopontin; PAI-1, plasminogen activator inhibitor; PGE, prostaglandin E; PI3K, phosphatidylinositol 3 kinase; PTEN, phosphatase and tensin homologue; RTK, receptor tyrosine kinase; TGFα(β) (R), transforming growth factor α(β)(receptor); uPA(R), urokinase plasminogen activator (receptor); VEGF, vascular endothelial growth factor; VHL, von Hippel Lindau. KEY WORDS: motility, proteolysis, signalling, angiogenesis, invasion Parallels in invasion and angiogenesisTaking a reductionist approach, we can consider that both tumour invasion and capillary sprouting require that cells successfully manage the following challenges: survival in ectopic environments where normal anti-apoptotic signals may be lacking; overcoming the "default" position of quiescence in adult differentiated cells (G 0 ) and activation of proliferation; modification of adhesive interactions with the extracellular matrix and surrounding cells enabling tissue plasticity; acquisition of migratory capacity and ability to respond to chemokine gradients and other soluble or immob...

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“…Therefore, HIF-1 is an attractive target for cancer therapy. 18 Several approaches have been used to inhibit HIF-1a expression and/or activity, which include antisense or siRNA strategies, 19,20 inhibition of proteins that modulate HIF-1 activity, [21][22][23][24] signal transduction pathways involved in HIF-1a activation [25][26][27] microtubules, topoisomerase I 28 or mechanisms not clearly defined. 29 A number of anticancer drugs have been shown to inhibit HIF, but none of these drugs have been shown to directly and specifically target HIF-1.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

Manohar

Padgaonkar

Jalota‐Badhwar

et al. 2011

Prostate Cancer Prostatic Dis

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BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation and controls genes involved in glycolysis, angiogenesis, migration and invasion. Overexpression of HIF-1a has been demonstrated in many common human cancers. METHODS:Luciferase reporter gene assay under hypoxia and normoxia was used to demonstrate transcriptional inhibition of HIF-1 by P276-00. Detailed studies such as western blotting, reverse-transcriptase-PCR and immunofluorescence were carried out to elucidate its mechanism of action. Cytotoxic potential of P276-00 under normoxia and hypoxia was determined on prostate cancer cells using CCK-8 assay, and cell-cycle analysis was carried out using flow cytometry. Antiangiogenic activity of P276-00 was demonstrated by migration assay and tube-formation assay. Efficacy study of P276-00 was performed in a PC-3 xenograft model.RESULTS: P276-00 inhibits transcriptional activation of HIF-1 under hypoxia. It suppressed hypoxia-mediated nuclear HIF-1a expression, as well as phosphorylation of Akt and 4E-BP1 and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor. Under hypoxia, P276-00 did not exhibit enhanced cytotoxic activity in prostate cancer cells but arrested them in the G2/M phase of the cell cycle. The tubular formation of human umbilical vein endothelial cells and migration of prostate cancer cells were also inhibited by P276-00 in vitro. In addition, it demonstrated significant in vivo efficacy in the PC-3 xenograft model. CONCLUSIONS:Given its low toxicity profile, its demonstrated antitumor activity and its potential to inhibit the HIF-1 pathway, P276-00 should be considered as antiangiogenic chemotherapy for prostate cancer.

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A Radicicol Derivative, KF58333, Inhibits Expression of Hypoxia‐inducible Factor‐1α and Vascular Endothelial Growth Factor, Angiogenesis and Growth of Human Breast Cancer Xenografts

Cited by 56 publications

References 29 publications

Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol

Reduction of Hypoxia-Induced Transcription through the Repression of Hypoxia-Inducible Factor-1α/Aryl Hydrocarbon Receptor Nuclear Translocator DNA Binding by the 90-kDa Heat-Shock Protein Inhibitor Radicicol

Parallels in invasion and angiogenesis provide pivotal points for therapeutic intervention

Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

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