5-alpha-reductase: 2012-10-28

2012年11月3日星期六

Aurora kinase B modulates chromosome alignment in mouse oocytes.

Aurora kinase B modulates chromosome alignment in mouse oocytes.

Mol Reprod Dev. 2009 Nov;76(11):1094-105

Authors: Shuda K, Schindler K, Ma J, Schultz RM, Donovan PJ

Abstract
The elevated incidence of aneuploidy in human oocytes warrants study of the molecular mechanisms regulating proper chromosome segregation. The Aurora kinases are a well-conserved family of serine/threonine kinases that are involved in proper chromosome segregation during mitosis and meiosis. Here we report the expression and localization of all three Aurora kinase homologs, AURKA, AURKB, and AURKC, during meiotic maturation of mouse oocytes. AURKA, the most abundantly expressed homolog, localizes to the spindle poles during meiosis I (MI) and meiosis II (MII), whereas AURKB is concentrated at kinetochores, specifically at metaphase of MI (Met I). The germ cell-specific homolog, AURKC, is found along the entire length of chromosomes during both meiotic divisions. Maturing oocytes in the presence of the small molecule pan-Aurora kinase inhibitor, ZM447439 results in defects in meiotic progression and chromosome alignment at both Met I and Met II. Over-expression of AURKB, but not AURKA or AURKC, rescues the chromosome alignment defect suggesting that AURKB is the primary Aurora kinase responsible for regulating chromosome dynamics during meiosis in mouse oocytes.

PMID: 19565641 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Aurora kinase family: a new target for anticancer drug.

Aurora kinase family: a new target for anticancer drug.

Recent Pat Anticancer Drug Discov. 2008 Jun;3(2):114-22

Authors: Macarulla T, Ramos FJ, Tabernero J

Abstract
Aurora kinases (AK) are the name given to a family of Serine/threonine (Ser/Thr) protein kinases. These proteins represent a novel family of kinases crucial for cell cycle control. The cell division process is one of the hallmarks of every living organism. Within the complete cell-cycle process, mitosis constitutes one of the most critical steps. The main purpose of mitosis is to segregate sister chromatics into two daughters cells. It is a complex biologic process, and errors in this mechanism can lead to genomic instability, a condition associated with tumorigenesis. This process is tightly regulated by several proteins, some of them acting as check-points that ultimately ensure the correct temporal and spatial coordination of this critical biologic process. Among this network of mitotic regulators, AK play a critical role in cellular division by controlling chromatid segregation. Three AK family members have been identified in mammalian cells: A, B, and C. These proteins are implicated in several vital events in mitosis. In experimental models, overexpression of AK can induce spindle defects, chromosome mis-segregation, and malignant transformation. Conversely, downregulation of AK expression cause mitotic arrest and apoptosis in tumor cell lines. The expression levels of human AK are increased in certain types of cancer including breast, colon, pancreatic, ovarian, and gastric tumors. This observation has lent an interest to this family of kinases as potential drug targets for development of new anticancer therapies. This review focuses in recent progress in the role of AK in tumorogenesis and the development of new anticancer drug against AK proteins. This manuscript also includes some relevant patents as well.

PMID: 18537754 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Requirement of aurora-A kinase in astral microtubule polymerization and spindle microtubule flux.

Requirement of aurora-A kinase in astral microtubule polymerization and spindle microtubule flux.

Cell Cycle. 2008 Apr 15;7(8):1104-11

Authors: Wang LH, Yan M, Xu DZ, Cao JX, Zhu XF, Zeng YX, Liu Q

Abstract
Mitotic Aurora-A kinase was found to be required for formation of bipolar spindle, ensuring accurate chromosome segregation in mitosis. Recently, Aurora-A was shown to promote Ran-GTP-induced spindle formation and astral microtubule development. Here, by selective immunodepletion, we showed that Aurora-A was required for centrosome- but not Ran-GTP-induced astral microtubule formation in Xenopus egg extracts. Aurora-A enhanced microtubule polymerization in both centrosome- and Ran-GTP-induced aster assemblies: shortening the timing of aster assembly and increasing the aster size. Indeed, adding of Aurora-A protein alone induced microtubule clustering, which was abrogated by Aurora kinase inhibitory small molecule ZM447439. In addition, we showed that Aurora-A was indispensable for Ran-GTP-induced bipolar spindle formation. Inhibition of Aurora-A activity by adding of kinase inactive dominant mutant led to spindle collapse and formation of monopolar spindle whereas minus-end motor protein dynein/dynactin inhibitor p50/dynamitin rescued the bipolar structure. Lastly, we revealed that Aurora-A was necessary for microtubule poleward flux and this requirement depended on kinase activity. Thus, we showed that Aurora-A promoted microtubule polymerization and maintained microtubule flux in ensuring proper bipolar spindle assembly.

PMID: 18414060 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells.

Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells.

J Biol Chem. 2007 Mar 9;282(10):6954-64

Authors: Gabrielli B, Chau YQ, Giles N, Harding A, Stevens F, Beamish H

Abstract
The spindle assembly checkpoint arrests cells in mitosis when defects in mitotic spindle assembly or partitioning of the replicated genome are detected. This checkpoint blocks exit from mitosis until the defect is rectified or the cell initiates apoptosis. In this study we have used caffeine to identify components of the mechanism that signals apoptosis in mitotic checkpoint-arrested cells. Addition of caffeine to spindle checkpoint-arrested cells induced >40% apoptosis within 5 h. It also caused proteasome-mediated destruction of cyclin B1, a corresponding reduction in cyclin B1/cdk1 activity, and reduction in MPM-2 reactivity. However, cells retained MAD2 staining at the kinetochores, an indication of continued spindle checkpoint function. Blocking proteasome activity did not block apoptosis, but continued spindle checkpoint function was essential for apoptosis. After systematically eliminating all known targets, we have identified p21-activated kinase PAK1, which has an anti-apoptotic function in spindle checkpoint-arrested cells, as a target for caffeine inhibition. Knockdown of PAK1 also increased apoptosis in spindle checkpoint-arrested cells. This study demonstrates that the spindle checkpoint not only regulates mitotic exit but apoptosis in mitosis through the activity of PAK1.

PMID: 17182611 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts.

Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts.

Mol Biol Cell. 2005 Mar;16(3):1305-18

Authors: Gadea BB, Ruderman JV

Abstract
The Aurora family kinases contribute to accurate progression through several mitotic events. ZM447439 ("ZM"), the first Aurora family kinase inhibitor to be developed and characterized, was previously found to interfere with the mitotic spindle integrity checkpoint and chromosome segregation. Here, we have used extracts of Xenopus eggs, which normally proceed through the early embryonic cell cycles in the absence of functional checkpoints, to distinguish between ZM's effects on the basic cell cycle machinery and its effects on checkpoints. ZM clearly had no effect on either the kinetics or amplitude in the oscillations of activity of several key cell cycle regulators. It did, however, have striking effects on chromosome morphology. In the presence of ZM, chromosome condensation began on schedule but then failed to progress properly; instead, the chromosomes underwent premature decondensation during mid-mitosis. ZM strongly interfered with mitotic spindle assembly by inhibiting the formation of microtubules that are nucleated/stabilized by chromatin. By contrast, ZM had little effect on the assembly of microtubules by centrosomes at the spindle poles. Finally, under conditions where the spindle integrity checkpoint was experimentally induced, ZM blocked the establishment, but not the maintenance, of the checkpoint, at a point upstream of the checkpoint protein Mad2. These results show that Aurora kinase activity is required to ensure the maintenance of condensed chromosomes, the generation of chromosome-induced spindle microtubules, and activation of the spindle integrity checkpoint.

PMID: 15616188 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

2012年11月2日星期五

Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.

Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.

Cell Cycle. 2008 Oct;7(20):3187-93

Authors: Ganguly A, Bhattacharya R, Cabral F

Abstract
MCAK, a kinesin related motor protein with microtubule depolymerizing activity, is known to play an important role in spindle assembly and correcting errors in mitotic chromosome alignment. Experiments to determine how cellular levels of the protein are regulated demonstrate that MCAK accumulates during cell cycle progression, reaches a maximum at G(2)/M phase, and is rapidly degraded by the proteasome during mitosis. Immunofluorescence microscopy further indicates that MCAK largely disappears from kinetochores and spindle poles at the metaphase to anaphase transition. A phosphorylated form of MCAK appears during mitosis and seems to be preferentially degraded, but degradation does not appear to depend on Aurora B, a kinase reported to be involved in regulating the error correcting activity of the protein. These studies indicate that MCAK activity is limited during the latter stages of mitosis by protein degradation, and argue against a role for the protein in anaphase chromosome movement.

PMID: 18843200 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

The Ipl1/Aurora kinase family: methods of inhibition and functional analysis in mammalian cells.

The Ipl1/Aurora kinase family: methods of inhibition and functional analysis in mammalian cells.

Methods Mol Biol. 2005;296:371-81

Authors: Ditchfield C, Keen N, Taylor SS

Abstract
The Ipl1/Aurora family of protein kinases are required for accurate chromosome segregation. Because members of this family are often overexpressed in human tumors, they have recently received much attention, both from the academic community and the pharmaceutical industry. Indeed, two small molecule Aurora kinase inhibitors have recently been described. In this chapter, we describe several methods for investigating the function of the Aurora kinases, focusing on Aurora B. We describe the use of the small-molecule inhibitor ZM447439, RNA interference, and overexpression of a catalytic mutant. All of these methods have proved useful in studying Aurora B as well as validating it as a potential anticancer drug target. However, while all three methods are useful for probing the function of Aurora B, each has inherent advantages and disadvantages. Furthermore, because the mechanism underlying the inhibition is different in each case, caution must be taken when interpreting the data.

PMID: 15576945 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines.

ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines.

Neuroendocrinology. 2010;91(2):121-30

Authors: Georgieva I, Koychev D, Wang Y, Holstein J, Hopfenm�ller W, Zeitz M, Grabowski P

Abstract
Background: Therapeutic approaches to gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still not satisfactory. A new direction in treatment options could be the novel aurora kinase inhibitor ZM447439, which was previously reported to interfere with the mitotic spindle integrity checkpoint and chromosome segregation, but does not interfere with other kinases when used up to 5 muM. Methods: We evaluated the antineoplastic effects of ZM447439 on growth and apoptosis of the GEP-NET cell lines BON, QGP-1 and MIP-101, representing the different malignant tumor types, using standard cell biological tests as crystal violet assays, caspase activation, DNA fragmentation and cell cycle analysis. Results: ZM447439 dose-dependently inhibited proliferation of all three cell lines with IC(50) values in the nanomolar to low micromolar range. Moreover, aurora kinase inhibition by ZM447439 potently induced apoptosis, which was accompanied by DNA fragmentation and caspase 3 and 7 activation. Furthermore, we observed cell cycle arrest at G(0)/G(1) phase as well as a block in G(2)/M transition. In addition, combined treatment with the chemotherapeutic agents streptozocin and cisplatin augmented significantly the antiproliferative effects of those agents. Conclusion: Aurora kinase inhibition by ZM447439 seems to be a promising new therapeutic approach in GEP-NETs, which should be evaluated in further clinical trials.

PMID: 19923785 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells.

Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells.

J Biol Chem. 2007 Mar 9;282(10):6954-64

Authors: Gabrielli B, Chau YQ, Giles N, Harding A, Stevens F, Beamish H

PMID: 17182611 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Investigating the role of Aurora kinases in RAS signaling.

Investigating the role of Aurora kinases in RAS signaling.

J Cell Biochem. 2009 Jan 1;106(1):33-41

Authors: Kosik A, Bekier ME, Katusin JD, Kaur H, Zhou X, Diakonova M, Chadee DN, Taylor WR

Abstract
Activating ras mutations are frequently found in malignant tumors of the pancreas, colon, lung and other tissues. RAS activates a number of downstream pathways that ultimately cause cellular transformation. Several recent studies suggested that one of those pathways involves Aurora kinases. Overexpression of Aurora-B kinase can augment transformation by oncogenic RAS, however the mechanism was not determined. The cooperative effect of high levels of Aurora kinase is important since this kinase is frequently overexpressed in human tumors. We have used two Aurora kinase inhibitors to test their effect on RAS signaling. We find that these inhibitors have no effect on the phosphorylation of MEK1/2 or MAPK in response to RAS. Furthermore, inhibiting Aurora kinases in human cancer cells with or without activated RAS did not change the length of the cell cycle nor induce apoptosis suggesting that these kinases do not play a direct role in these key cellular responses to activated RAS. Overexpression of Aurora B can cause cells to become polyploid. Also, inducing polyploidy with cytochalasin D was reported to induce neoplastic transformation, suggesting that Aurora overexpression may cooperate with RAS indirectly by inducing polyploidy. We find that inducing polyploidy with cytochalasin D or blebbistatin does not enhance transformation by oncogenic RAS. Our observations argue against a direct role for Aurora kinases in the RAS-MAPK pathway, and suggest that the polyploid state does not enhance transformation by RAS.

PMID: 19009561 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

2012年11月1日星期四

Aurora kinase family: a new target for anticancer drug.

Aurora kinase family: a new target for anticancer drug.

Recent Pat Anticancer Drug Discov. 2008 Jun;3(2):114-22

Authors: Macarulla T, Ramos FJ, Tabernero J

PMID: 18537754 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Inhibition of survivin and aurora B kinase sensitizes mesothelioma cells by enhancing mitotic arrests.

Inhibition of survivin and aurora B kinase sensitizes mesothelioma cells by enhancing mitotic arrests.

Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1519-25

Authors: Kim KW, Mutter RW, Willey CD, Subhawong TK, Shinohara ET, Albert JM, Ling G, Cao C, Gi YJ, Lu B

Abstract
PURPOSE: Survivin, a member of the inhibitor of apoptosis gene family, has also been shown to regulate mitosis. It binds Aurora B kinase and the inner centromere protein to form the chromosome passenger complex. Both Aurora B and survivin are overexpressed in many tumors. In this study, we examined whether irradiation affected survivin and Aurora B expression in mesothelioma cells, and how inhibition of these molecules affected radiosensitivity.
METHODS AND MATERIALS: ZM447439 and survivin antisense oligonucleotides were used to inhibit survivin and Aurora B kinase respectively. Western blot was performed to determine the expression of survivin, Aurora B, phosphorylated-histone H3 (Ser 10), and caspase cleavage. Multinucleated cells were counted using flow cytometry, and cell survival after treatment was determined using clonogenic assay.
RESULTS: At 3-Gy irradiation an increase was observed in levels of survivin and Aurora B as well as the kinase activity of Aurora B, with an increase in G2/M phase. The radiation-induced upregulation of these molecules was effectively attenuated by antisense oligonucleotides against survivin and a small-molecule inhibitor of Aurora B, ZM447439. Dual inhibition of survivin and Aurora B synergistically radiosensitized mesothelioma cells with a dose enhancement ratio of 2.55. This treatment resulted in increased formation of multinucleated cells after irradiation but did not increase levels of cleaved caspase 3.
CONCLUSION: Inhibition of survivin and Aurora B induces mitotic cell arrest in mesothelioma cells after irradiation. These two proteins may be potential therapeutic targets for the enhancement of radiotherapy in malignant pleural mesothelioma.

PMID: 17394948 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

The expanding role of somatostatin analogs in the management of neuroendocrine tumors.

The expanding role of somatostatin analogs in the management of neuroendocrine tumors.

Gastrointest Cancer Res. 2012 Sep;5(5):161-8

Authors: Wolin EM

Abstract
BACKGROUND: Neuroendocrine tumors (NETs) are neoplasms arising most often in the GI tract, pancreas, or lung. Diagnosis of NETs is often delayed until the disease is advanced, because of the variable and nonspecific nature of the initial symptoms. Surgical resection for cure is therefore not an option for most patients.
METHODS: Somatostatin analogues represent the cornerstone of therapy for patients with NETs. This article reviews the important role that somatostatin analogues continue to play in the treatment of patients with NETs.
RESULTS: Octreotide was the first somatostatin analogue to be developed; more than 30 years of data have accumulated demonstrating its efficacy and safety. Lanreotide is another somatostatin analogue in clinical use, and pasireotide is a promising somatostatin analogue in development. Newer long-acting depot formulations are now available offering once-monthly administration. Although octreotide was initially developed for symptom control, recent results indicate that it also has an antiproliferative effect, significantly increasing time to progression in patients with midgut NETs. Combinations of octreotide with other targeted therapies may further improve patient outcomes. Findings in recent studies of the combination of octreotide and the mTOR inhibitor everolimus are encouraging. The combinations of octreotide with other agents (eg, interferon-?, bevacizumab, cetuximab, AMG-706, and sunitinib) are being investigated.
CONCLUSIONS: Somatostatin analogues have been used to treat the symptoms of NETs for decades and also have an antineoplastic effect, markedly prolonging progression-free survival. Somatostatin analogues are likely to remain the cornerstone of treatment for most patients with advanced NETs. Promising new combination therapies are undergoing clinical investigation.

PMID: 23112884 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.

J Cancer Res Clin Oncol. 2012 Mar;138(3):405-14

Authors: Borges KS, Castro-Gamero AM, Moreno DA, da Silva Silveira V, Brassesco MS, de Paula Queiroz RG, de Oliveira HF, Carlotti CG, Scrideli CA, Tone LG

Abstract
BACKGROUND: Glioblastoma remains one of the most devastating human malignancies, and despite therapeutic advances, there are no drugs that significantly improve the patient survival. Altered expression of the Aurora kinases was found in different malignancies, and their inhibition has been studied in cancer therapy. In this study, we analyzed the expression of Aurora A and Aurora B in glioblastoma samples and also analyzed whether the effects of Aurora kinase inhibition were associated with temozolomide or not on cell lines and primary cultures of glioblastoma.
MATERIALS AND METHODS: RT-PCR assays were used to determine the mRNA expression in glioblastoma tumor samples and in the cell lines. Cell proliferation was measured by XTT assay, and apoptosis was determined by flow cytometry. Drug combination analyses were made based in Chou-Talalay method. Gamma radiation for clonogenic survival used the doses of 2, 4 and 6 Gy. Changes in Aurora B level were assessed by Western blot analysis.
RESULTS: Aurora A and B were expressed in glioblastoma samples as well as in the glioblastoma cell lines (n = 6). Moreover, ZM447439, a selective Aurora kinase inhibitor, decreased the proliferation separately and synergistically with temozolomide in primary cultures and cell lines of glioblastoma. ZM also enhanced the effects of radiation on the two cell lines studied (U343 and U251), mainly when associated with TMZ in U343 cells. Treatment with ZM induced apoptotic cell death and diminished Aurora B protein level.
CONCLUSIONS: These data suggest that Aurora kinase inhibition may be a target for glioblastoma treatment and could be used as adjuvant to chemo- and radiotherapy.

PMID: 22160182 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

2012年10月31日星期三

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit.

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit.

Mol Cancer Ther. 2009 Jun;8(6):1646-54

Authors: Bekier ME, Fischbach R, Lee J, Taylor WR

Abstract
Cell death induced by agents that disrupt microtubules can kill cells by inducing a prolonged mitotic block. This mitotic block is dependent on the spindle assembly checkpoint, a surveillance system that ensures the bipolar attachment of chromosomes to the mitotic spindle before the onset of anaphase. Under some conditions, the spindle assembly checkpoint can become weakened, allowing cells to exit mitosis despite the presence of chromosomes that are not properly attached to the mitotic spindle. Here, we use an Aurora kinase inhibitor to drive mitotic exit and test the effect of mitotic arrest length on death in the subsequent interphase. Cells that are blocked in mitosis for >15 h die shortly after exiting from mitosis, whereas cells that exit after being blocked for <15 h show variable fates, with some living for days after exiting mitosis. Cells blocked in mitosis by either Taxol or epothilone B are acutely sensitive to the death ligand tumor necrosis factor-related apoptosis-inducing ligand, suggesting that prolonged mitosis allows the gradual accumulation of internal death signals, rendering cells hypersensitive to additional prodeath cues. Death under these conditions is initiated while cyclin B1 is still present, indicating that cells are in mitosis. Our experiments suggest that there is a point of no return during prolonged mitotic block after which mitotic exit can no longer block death.

PMID: 19509263 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Validating Aurora B as an anti-cancer drug target.

Validating Aurora B as an anti-cancer drug target.

J Cell Sci. 2006 Sep 1;119(Pt 17):3664-75

Authors: Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, Keen NJ, Taylor SS

Abstract
The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery.

PMID: 16912073 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Exp Cell Res. 2009 Apr 15;315(7):1085-99

Authors: Dreier MR, Grabovich AZ, Katusin JD, Taylor WR

Abstract
Aurora kinases are essential for mitosis and are candidate targets of novel chemotherapeutic agents. The inhibitors ZM447439, MK-0457 (VX-680) as well as Hesperadin have been used to dissect the roles of Aurora kinases in the cell cycle and have been tested clinically for the treatment of cancer. Here we have carried out a detailed kinetic analysis of two isogenic cell lines differing in p53 function and have compared the effects of ZM447439 and VE-465 (related to MK-0457). We find that p53 is needed for efficient cell cycle arrest when Aurora kinases are inhibited by either ZM447439 or VE-465. However, the p53-induced cell cycle block is neither immediate nor absolute. ZM447439 induced the localized accumulation of gammaH2A.X indicating that p53 induction by this drug occurs in response to DNA damage. Our analysis of the long-term effects of ZM447439 indicates that cells can evade killing by the drug, but not via a classical drug-resistance mechanism. Several mechanisms to explain how cells may evade killing by Aurora kinase inhibitors are described.

PMID: 19233169 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Dawn of Aurora kinase inhibitors as anticancer drugs.

Dawn of Aurora kinase inhibitors as anticancer drugs.

Expert Opin Investig Drugs. 2004 Sep;13(9):1199-201

Authors: Doggrell SA

Abstract
With the current standard chemotherapy regimens only approximately 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.

PMID: 15330750 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Short and long-term tumor cell responses to Aurora kinase inhibitors.

Exp Cell Res. 2009 Apr 15;315(7):1085-99

Authors: Dreier MR, Grabovich AZ, Katusin JD, Taylor WR

PMID: 19233169 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

2012年10月30日星期二

Regulation of the meiotic prophase I to metaphase I transition in mouse spermatocytes.

Regulation of the meiotic prophase I to metaphase I transition in mouse spermatocytes.

Chromosoma. 2008 Oct;117(5):471-85

Authors: Sun F, Handel MA

Abstract
The meiotic prophase I to metaphase I transition (G2/MI) involves disassembly of synaptonemal complex (SC), chromatin condensation, and final compaction of morphologically distinct MI bivalent chromosomes. Control of these processes is poorly understood. The G2/MI transition was experimentally induced in mouse pachytene spermatocytes by okadaic acid (OA), and kinetic analysis revealed that disassembly of the central element of the SC occurred very rapidly after OA treatment, before histone H3 phosphorylation on Ser10. These events were followed by relocalization of SYCP3 and final condensation of bivalents. Enzymatic control of these G2/MI transition events was studied using small molecule inhibitors: butyrolactone I (BLI), an inhibitor of cyclin-dependent kinases (CDKs) and ZM447439 (ZM), an inhibitor of aurora kinases (AURKs). The formation of highly condensed MI bivalents and disassembly of the SC are regulated by both CDKs and AURKs. AURKs also mediate phosphorylation of histone H3 in meiosis. However, neither BLI nor ZM inhibited disassembly of the central element of the SC. Thus, despite evidence that the metaphase promoting factor is a universal regulator of the onset of cell division, desynapsis, the first and key step of the G2/MI transition, occurs independently of BLI-sensitive CDKs and ZM-sensitive AURKs.

PMID: 18563426 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

Biochem Pharmacol. 2012 Oct 4;

Authors: Hasinoff BB, Wu X, Nitiss JL, Kanagasabai R, Yalowich JC

Abstract
Dovitinib (TKI258/CHIR258) is a multi-kinase inhibitor in phase III development for the treatment of several cancers. Dovitinib is a benzimidazole-quinolinone compound that structurally resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Dovitinib bound to DNA as shown by its ability to increase the DNA melting temperature and by increases in its fluorescence spectrum that occurred upon the addition of DNA. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could reasonably be accommodated in the DNA minor groove. Because DNA binders are often topoisomerase I (EC 5.99.1.2) and topoisomerase II (EC 5.99.1.3) inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited the catalytic decatenation activity of topoisomerase II?. It also inhibited the DNA-independent ATPase activity of yeast topoisomerase II which suggested that it interacted with the ATP binding site. Using isolated human topoisomerase II?, dovitinib stabilized the enzyme-cleavage complex and acted as a topoisomerase II? poison. Dovitinib was also found to be a cellular topoisomerase II poison in human leukemia K562 cells and induced double-strand DNA breaks in K562 cells as evidenced by increased phosphorylation of H2AX. Finally, dovitinib inhibited the topoisomerase I-catalyzed relaxation of plasmid DNA and acted as a cellular topoisomerase I poison. In conclusion, the cell growth inhibitory activity and the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also, in part, from its ability to target topoisomerase I and topoisomerase II.

PMID: 23041231 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

The Ipl1/Aurora kinase family: methods of inhibition and functional analysis in mammalian cells.

The Ipl1/Aurora kinase family: methods of inhibition and functional analysis in mammalian cells.

Methods Mol Biol. 2005;296:371-81

Authors: Ditchfield C, Keen N, Taylor SS

PMID: 15576945 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Validating Aurora B as an anti-cancer drug target.

Validating Aurora B as an anti-cancer drug target.

J Cell Sci. 2006 Sep 1;119(Pt 17):3664-75

Authors: Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, Keen NJ, Taylor SS

PMID: 16912073 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

ZM447439, the Aurora kinase B inhibitor, suppresses the growth of cervical cancer SiHa cells and enhances the chemosensitivity to cisplatin.

ZM447439, the Aurora kinase B inhibitor, suppresses the growth of cervical cancer SiHa cells and enhances the chemosensitivity to cisplatin.

J Obstet Gynaecol Res. 2011 Jun;37(6):591-600

Authors: Zhang L, Zhang S

Abstract
AIM: To investigate the effects of an Aurora kinase B inhibitor (ZM447439) on the cervical cancer cell line SiHa and chemotherapy of cisplatin (cDDP).
MATERIALS & METHODS: Detected Aurora-B protein in different tissues of the cervix by immunohistochemistry and then analyzed the relationship between Aurora B protein and clinical parameters of cervical cancer. The effect and synergistic effect of ZM447439 and cDDP on proliferation of SiHa cells was tested by MTT. The changes of cell cycle and apoptosis were detected by flow cytometry. Aurora-B, histone H3 phosphorylation (H3-P) protein, human papillomavirus16 E6 (HPV16E6) and BCL-2, P53, VEGF protein were detected by Western blot.
RESULTS: The positive rate of Aurora-B expression was the highest in cervical cancer and had no significant correlation with clinical stage, lymph node metastasis and age. ZM447439 can reduce the number of SiHa cells, increase the volume of cells and lead to apoptosis. The growth of SiHa cells treated with ZM447439, cDDP and the combination of both was inhibited in dose- and time-dependent manners. The inhibition rate of the combined treatment is significantly higher than that of two other single drug groups (P < 0.05). The synergistic effect is observed in the combined therapy. S-phase arrest and early apoptosis has become more evident in the combined treatment. ZM447439 significantly inhibited the expression of Aurora-B and H3-P protein (P < 0.05). ZM447439, cDDP and the combination of both reduced the expression of HPV16E6 and BCL-2 protein, raised P53 protein expression (P < 0.05), whose effects were more obvious in the combined therapy. cDDP could also reduce VEGF protein expression, but ZM447439 could not.
CONCLUSION: Our results suggest that Aurora-B may represent a valid target in cervical squamous carcinoma and has a synergistic effect with cDDP.

PMID: 21159048 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

2012年10月29日星期一

Aurora kinase B modulates chromosome alignment in mouse oocytes.

Aurora kinase B modulates chromosome alignment in mouse oocytes.

Mol Reprod Dev. 2009 Nov;76(11):1094-105

Authors: Shuda K, Schindler K, Ma J, Schultz RM, Donovan PJ

PMID: 19565641 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Molecular basis of drug resistance in aurora kinases.

Molecular basis of drug resistance in aurora kinases.

Chem Biol. 2008 Jun;15(6):552-62

Authors: Girdler F, Sessa F, Patercoli S, Villa F, Musacchio A, Taylor S

Abstract
Aurora kinases have emerged as potential targets in cancer therapy, and several drugs are currently undergoing preclinical and clinical validation. Whether clinical resistance to these drugs can arise is unclear. We exploited a hypermutagenic cancer cell line to select mutations conferring resistance to a well-studied Aurora inhibitor, ZM447439. All resistant clones contained dominant point mutations in Aurora B. Three mutations map to residues in the ATP-binding pocket that are distinct from the "gatekeeper" residue. The mutants retain wild-type catalytic activity and were resistant to all of the Aurora inhibitors tested. Our studies predict that drug-resistant Aurora B mutants are likely to arise during clinical treatment. Furthermore, because the plasticity of the ATP-binding pocket renders Aurora B insensitive to multiple inhibitors, our observations indicate that the drug-resistant Aurora B mutants should be exploited as novel drug targets.

PMID: 18559266 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.

J Cancer Res Clin Oncol. 2012 Mar;138(3):405-14

Authors: Borges KS, Castro-Gamero AM, Moreno DA, da Silva Silveira V, Brassesco MS, de Paula Queiroz RG, de Oliveira HF, Carlotti CG, Scrideli CA, Tone LG

PMID: 22160182 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Cloning, ligand-binding, and temporal expression of ecdysteroid receptors in the diamondback moth, Plutella xylostella.

Cloning, ligand-binding, and temporal expression of ecdysteroid receptors in the diamondback moth, Plutella xylostella.

BMC Mol Biol. 2012 Oct 19;13(1):32

Authors: Tang B, Dong W, Liang P, Zhou X, Gao X

Abstract
ABSTRACT: BACKGROUND: The diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), is a devastating pest of cruciferous crops worldwide, and has developed resistance to a wide range of insecticides, including diacylhydrazine-based ecdysone agonists, a highly selective group of molt-accelerating biopesticides targeting the ecdysone receptors.ResultIn this study, we cloned and characterized the ecdysone receptors from P. xylostella, including the two isoforms of EcR and a USP. Sequence comparison and phylogenetic analysis showed striking conservations among insect ecdysone receptors, especially between P. xylostella and other lepidopterans. The binding affinity of ecdysteroids to in vitro-translated receptor proteins indicated that PxEcRB isoform bound specifically to ponasterone A, and the binding affinity was enhanced by co-incubation with PxUSP (Kd =3.0+/-1.7 nM). In contrast, PxEcRA did not bind to ponasterone A, even in the presence of PxUSP. The expression of PxEcRB were consistently higher than that of PxEcRA across each and every developmental stage, while the pattern of PxUSP expression is more or less ubiquitous. CONCLUSIONS: Target site insensitivity, in which the altered binding of insecticides (ecdysone agonists) to their targets (ecdysone receptors) leads to an adaptive response (resistance), is one of the underlying mechanisms of diacylhydrazine resistance. Given the distinct differences at expression level and the ligand-binding capacity, we hypothesis that PxEcRB is the ecdysone receptor that controls the remodeling events during metamorphosis. More importantly, PxEcRB is the potential target site which is modified in the ecdysone agonist-resistant P. xylostella.

PMID: 23078528 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Neither Aurora B activity nor histone H3 phosphorylation is essential for chromosome condensation during meiotic maturation of porcine oocytes.

Neither Aurora B activity nor histone H3 phosphorylation is essential for chromosome condensation during meiotic maturation of porcine oocytes.

Biol Reprod. 2006 May;74(5):905-12

Authors: Jel�nkov� L, Kubelka M

Abstract
Aurora kinase B (AURKB) is a chromosomal passenger protein that is essential for a number of processes during mitosis. Its activity is regulated by association with two other passenger proteins, INCENP and Survivin, and by phosphorylation on Thr 232. In this study, we examine expression and phosphorylation on Thr-232 of AURKB during meiotic maturation of pig oocytes in correlation with histone H3 phosphorylation and chromosome condensation. We show that histone H3 phosphorylation on Ser-10, but not on Ser-28, correlates with progressive chromosome condensation during oocyte maturation; Ser-10 phosphorylation starts around the time of the breakdown of the nuclear envelope, with the maximal activity in metaphase I, whereas Ser-28 phosphorylation does not significantly change in maturing oocytes. Treatment of oocytes with 50 microM butyrolactone I (BL-I), an inhibitor of cyclin-dependent kinases, or cycloheximide (10 microg/ml), inhibitor of proteosynthesis, results in a block of oocytes in the germinal vesicle stage, when nuclear membrane remains intact; however, condensed chromosome fibers or highly condensed chromosome bivalents can be seen in the nucleoplasm of BL-I- or cycloheximide-treated oocytes, respectively. In these treated oocytes, no or only very weak AURKB activity and phosphorylation of histone H3 on Ser-10 can be detected after 27 h of treatment, whereas phosphorylation on Ser-28 is not influenced. These results suggest that AURKB activity and Ser-10 phosphorylation of histone H3 are not required for chromosome condensation in pig oocytes, but might be required for further processing of chromosomes during meiosis.

PMID: 16452462 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

2012年10月28日星期日

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.

Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.

J Cancer Res Clin Oncol. 2012 Mar;138(3):405-14

Authors: Borges KS, Castro-Gamero AM, Moreno DA, da Silva Silveira V, Brassesco MS, de Paula Queiroz RG, de Oliveira HF, Carlotti CG, Scrideli CA, Tone LG

PMID: 22160182 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.

Mol Cancer Ther. 2007 Jun;6(6):1851-7

Authors: Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H

Abstract
The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia.

PMID: 17541033 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Cloning, ligand-binding, and temporal expression of ecdysteroid receptors in the diamondback moth, Plutella xylostella.

Cloning, ligand-binding, and temporal expression of ecdysteroid receptors in the diamondback moth, Plutella xylostella.

BMC Mol Biol. 2012 Oct 19;13(1):32

Authors: Tang B, Dong W, Liang P, Zhou X, Gao X

PMID: 23078528 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells.

Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells.

J Biol Chem. 2007 Mar 9;282(10):6954-64

Authors: Gabrielli B, Chau YQ, Giles N, Harding A, Stevens F, Beamish H

PMID: 17182611 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Cyclosporine A Impairs Norepinephrine-Induced Vascular Contractility.

Cyclosporine A Impairs Norepinephrine-Induced Vascular Contractility.

Kidney Blood Press Res. 2012 Oct 19;35(6):655-662

Authors: Bergler T, Resch M, Reinhold SW, Birner C, Jungbauer CG, Griese DP, Schmid P, Banas B, Endemann D

Abstract
Usage of cyclosporine A (CsA) after kidney transplantation may be associated with development of nephrotoxicity and vasculopathy, but the mechanisms by which CsA causes vascular dysfunction are still under scrutiny. We established a transplantation model and investigated the effect of CsA on vascular contractility with the aid of a pressurized myograph in comparison with control and unilaterally nephrectomized rats. Results were correlated with mRNA expression studies of ?- and ?-adrenoreceptors, in mesenteric resistance arteries versus the thoracic aorta. Consequences of everolimus on functional properties as well as adrenoreceptor expression were also studied. CsA significantly downregulated expression of mesenteric adrenoreceptors, whereas no effect on aortic adrenoreceptors was seen. Administration of everolimus had no influence on mRNA adrenoreceptor expression in mesenteric resistance arteries. Furthermore, contractile responses of mesenteric resistance arteries to norepinephrine were markedly reduced after treatment with CsA, while there was no difference in contraction by endothelin. Everolimus did not alter the contractility response at all. In summary, norepinephrine-induced, but not endothelin-induced, contractile responses of mesenteric resistance arteries are blunted in CsA-treated rats. This finding was accompanied by a marked downregulation of adrenoreceptors in mesenteric resistance arteries and was limited to the usage of CsA.

PMID: 23095665 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

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