5-alpha-reductase: 2012-11-04

2012年11月10日星期六

Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase.

Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase.

FEBS Lett. 2005 Jun 20;579(16):3385-91

Authors: Yang H, Burke T, Dempsey J, Diaz B, Collins E, Toth J, Beckmann R, Ye X

Abstract
We investigated why treatment of cells with dual aurora A and B kinase inhibitors produces phenotypes identical to inactivation of aurora B. We found that dual aurora kinase inhibitors in fact potently inhibit cellular activities of both kinases, indicating that inactivation of aurora B bypasses aurora A in mitosis. RNAi experiments further established that inactivation of aurora B indeed bypasses the requirement for aurora A and leads to polyploidy. Inactivation of aurora A activates checkpoint kinase BubR1 in an aurora B-dependent manner. Our results thus show that aurora B is responsible for mitotic arrest in the absence of aurora A.

PMID: 15922328 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

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]

c-met inhibitors zm-447439 rad001

Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.

Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.

Haematologica. 2008 May;93(5):662-9

Authors: Walsby E, Walsh V, Pepper C, Burnett A, Mills K

Abstract
BACKGROUND: Aurora kinases play an essential role in the orchestration of chromosome separation and cytokinesis during mitosis. Small-molecule inhibition of the aurora kinases has been shown to result in inhibition of cell division, phosphorylation of histone H3 and the induction of apoptosis in a number of cell systems. These characteristics have led aurora kinase inhibitors to be considered as potential therapeutic agents.
DESIGN AND METHODS: Aurora kinase gene expression profiles were assessed in 101 samples from patients with acute myeloid leukemia. Subsequently, aurora kinase inhibitors were investigated for their in vitro effects on cell viability, histone H3 phosphorylation, cell cycle and morphology in acute myeloid leukemia cell lines and primary acute myeloid leukemia samples.
RESULTS: The aurora kinase inhibitors AZD1152-HQPA and ZM447439 induced growth arrest and the accumulation of hyperploid cells in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. Furthermore, both agents inhibited histone H3 phosphorylation and this preceded perturbations in cell cycle and the induction of apoptosis. Single cell cloning assays were performed on diploid and polyploid cells to investigate their colony-forming capacities. Although the polyploid cells showed a reduced capacity for colony formation when compared with their diploid counterparts, they were consistently able to form colonies.
CONCLUSIONS: AZD1152-HQPA- and ZM447439 are effective apoptosis-inducing agents in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. However, their propensity to induce polyploidy does not inevitably result in apoptosis.

PMID: 18367484 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Aurora B is required for mitotic chromatin-induced phosphorylation of Op18/Stathmin.

Aurora B is required for mitotic chromatin-induced phosphorylation of Op18/Stathmin.

Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4493-8

Authors: Gadea BB, Ruderman JV

Abstract
Oncoprotein 18/Stathmin (Op18) is a microtubule-destabilizing protein that is inhibited by phosphorylation in response to many types of signals. During mitosis, phosphorylation of Op18 by cdc2 is necessary but not sufficient for Op18 inhibition. The presence of mitotic chromosomes is additionally required and involves phosphorylation of Ser-16 in Xenopus Op18 (and/or Ser-63 in human). Given that Ser-16 is an excellent Aurora A (Aur-A) kinase consensus phosphorylation site and the Aurora kinase inhibitor ZM447439 (ZM) blocks phosphorylation in the activation loop of Aur-A, we asked whether either Aur-A or Aurora B (Aur-B) might regulate Op18. We find that ZM blocks the ability of mitotic chromatin to induce Op18 hyperphosphorylation in Xenopus egg extracts. Depletion of Aur-B, but not Aur-A, blocks hyperphosphorylation of Op18, and chromatin assembled in the absence of Aur-B fails to induce hyperphosphorylation. These results suggest that Aur-B, which concentrates at centromeres of metaphase chromosomes, contributes to localized regulation of Op18 during the process of spindle assembly.

PMID: 16537398 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

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]

coxinhibitors c-met inhibitors zm-447439

2012年11月9日星期五

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]

ecdysone chir-258 dovitinib

Geminin overexpression induces mammary tumors via suppressing cytokinesis.

Geminin overexpression induces mammary tumors via suppressing cytokinesis.

Oncotarget. 2011 Dec;2(12):1011-27

Authors: Blanchard Z, Malik R, Mullins N, Maric C, Luk H, Horio D, Hernandez B, Killeen J, Elshamy WM

Abstract
Aneuploidy plays an important role in the development of cancer. Here, we uncovered an oncogenic role for geminin in mitotic cells. In addition to chromatin, tyrosine phosphorylated geminin also localizes to centrosome, spindle, cleavage furrow and midbody during mitosis. Geminin binding to Aurora B prevents its binding to INCENP, and thus activation leading to lack of histone H3-(serine 10) phosphorylation, chromosome condensation failure, aborted cytokinesis and the formation of aneuploid, drug resistance cells. Geminin overexpressing human mammary epithelial cells form aneuploid, aggressive tumors in SCID mice. Geminin is overexpressed in more than half of all breast cancers analyzed. The current study reveals that geminin is a genuine oncogene that promotes cytokinesis failure and production of aneuploid, aggressive breast tumors when overexpressed and thus a worthy therapeutic target (oncotarget) for aggressive breast cancer.

PMID: 22184288 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Protective role of 20-OH ecdysone on lipid profile and tissue fatty acid changes in Streptozotocin induced diabetic rats.

Protective role of 20-OH ecdysone on lipid profile and tissue fatty acid changes in Streptozotocin induced diabetic rats.

Eur J Pharmacol. 2012 Oct 27;

Authors: Sundaram R, Naresh R, Shanthi P, Sachdanandam P

Abstract
Hyperlipidemia is an associated complication of diabetes mellitus. The association of hyperglycemia with an alteration of lipid parameters presents a major risk for cardiovascular complications in diabetes. The present study was designed to examine the antihyperlipidemic effect of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats. The levels of blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein,high density lipoprotein, lipoprotein lipase, lecithin cholesterol acyl transferase, 3-hydroxy 3-methylglutaryl coenzyme A reductase and fatty acid composition were estimated in plasma, liver and kidneys of control and experimental groups of rats. Oral administration of 20-OH ecdysone at a dose of 5mg/kg bodyweight per day to STZ-induced diabetic rats for a period of 30 days resulted in a significant reduction in fasting blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, 3-hydroxy 3-methylglutaryl coenzyme A reductase and elevation of high density lipoprotein,lipoprotein lipase and lecithin cholesterol acyl transferasein comparison with diabetic untreated rats. Moreover, administration of 20-OH ecdysone to diabetic rats also decreased the concentrations of fatty acids, viz., palmitic, stearic (16:1) and oleic acid (18:1), whereas linolenic (18:3) and arachidonic acid (20:4) were elevated. The antihyperlipidemic effect of 20-OH ecdysone was compared with glibenclamide a well-known antihyperglycemic drug. The result of the present study indicates that 20-OH ecdysone showed an antihyperlipidemic effect in addition to its antidiabetic effect in experimental diabetes.

PMID: 23110815 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin.

Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin.

Carcinogenesis. 2012 Mar;33(3):492-500

Authors: Yoon MJ, Park SS, Kang YJ, Kim IY, Lee JA, Lee JS, Kim EG, Lee CW, Choi KS

Abstract
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. In this study, we examined whether Aurora B, which is frequently overexpressed in cancer cells, is associated with TRAIL resistance. The protein levels of Aurora B were higher in TRAIL-resistant cancer cell lines than in TRAIL-sensitive cancer cell lines. Exogenously expressed Aurora B attenuated TRAIL-induced apoptosis in the tested TRAIL-sensitive cancer cell lines, whereas the small interfering RNA-mediated suppression of Aurora B expression stimulated TRAIL-mediated apoptosis in the tested TRAIL-resistant cancer cell lines. Furthermore, combined treatment with TRAIL and ZM447439, a specific inhibitor of Aurora B, synergistically induced apoptosis in various TRAIL-resistant cancer cells, suggesting that this combined regimen may represent an attractive strategy for effectively treating TRAIL-resistant malignant cancers. Mechanistically, the inhibition of Aurora B activity in various cancer cells commonly downregulated survivin protein levels and potentiated the activation of caspase-3. In addition, Aurora B inhibition induced mitotic catastrophe, which also contributed to the sensitization of cells to TRAIL-mediated apoptosis. Interestingly, forced overexpression of Aurora B increased the protein levels of survivin, but not those of a non-phosphorylatable survivin mutant in which threonine 117 was replaced by alanine, indicating that phosphorylation of survivin is required for this effect. Furthermore, TRAIL-induced apoptosis in MDA-MB-435S cells was attenuated by wild-type survivin but not by the non-phosphorylatable survivin mutant. Collectively, our results demonstrate that Aurora B confers TRAIL resistance to cancer cells via phosphorylation of survivin.

PMID: 22159225 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

Exp Cell Res. 2006 Nov 1;312(18):3459-70

Authors: Wang Y, Toppari J, Parvinen M, Kallio MJ

Abstract
In somatic cells, integrity of cell division is safeguarded by the spindle checkpoint, a signaling cascade that delays the separation of sister chromatids in the presence of misaligned chromosomes. Aurora kinases play important roles in this process by promoting centrosome maturation, chromosome bi-orientation, spindle checkpoint signaling, and cytokinesis. To investigate the functions of Aurora kinases in male meiosis, we applied a small molecule Aurora inhibitor, ZM447439, to seminiferous tubules in vitro. Primary and secondary spermatocytes exposed to ZM447439 exhibit defects in the spindle morphology and fail to align their chromosomes at the metaphase plate. Moreover, the treated spermatocytes undergo a forced exit from the meiotic M-phase without cytokinesis. These results suggest that the activities of Aurora kinases are required for normal spindle assembly as well as for establishment and maintenance of proper microtubule-kinetochore attachments and spindle checkpoint signaling in male mammalian meiosis.

PMID: 16962097 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

2012年11月8日星期四

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

Exp Cell Res. 2006 Nov 1;312(18):3459-70

Authors: Wang Y, Toppari J, Parvinen M, Kallio MJ

PMID: 16962097 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Low-dose celecoxib improves coronary function after acute myocardial ischaemia in rabbits.

Low-dose celecoxib improves coronary function after acute myocardial ischaemia in rabbits.

Clin Exp Pharmacol Physiol. 2012 Mar;39(3):233-40

Authors: Zhao M, He X, Zhao M, Bi XY, Zhang HL, Yu XJ, Liu JJ, Li DL, Ma X, Zang WJ

Abstract
The role of celecoxib in cardiovascular events remains contentious. The aim of the present study was to investigate the effects of celecoxib in acute myocardial ischaemia (AMI) in rabbits in comparison with those of another non-steroidal anti-inflammatory drug, namely aspirin. Male New Zealand white rabbits were divided into four groups: (i) a sham-operated group; (ii) an AMI group, in which the left anterior descending coronary arteries were occluded for 60�min; (iii) the celecoxib�+�AMI group, pretreated with 3�mg/kg celecoxib, twice a day, for 3�days before AMI induction; and (iv) the aspirin�+�AMI group, pretreated with 12.5�mg/kg aspirin, twice a day, for 3�days before AMI induction. Haemodynamic parameters were monitored using a multichannel physiological recorder. Serum levels of creatine kinase (CK), malondialdehyde (MDA), cyclo-oxygenase-2 (COX-2), tumour necrosis factor (TNF)-?, total nitrate/nitrite (NO(x) ), nitric oxide synthase (NOS) and myocardial infarct size were determined. Changes in isometric tension of isolated coronary rings were recorded by a myograph system. Compared with the sham group, the AMI group had lower blood pressure, higher left ventricular (LV) end-diastolic pressure, depressed maximum dP/dt of LV pressure, a larger infarct size and higher CK and MDA levels. Celecoxib, but not aspirin, pretreatment significantly ameliorated these effects of AMI. Celecoxib reversed AMI-induced increases in COX-2 levels to a similar extent as aspirin. Pretreatment with celecoxib resulted in a significant reduction in TNF-? levels and an increase in NO(x) and NOS levels compared with the AMI group. The dysfunctional vasoconstriction and vasodilation of coronary arteries were ameliorated by celecoxib administration. 4. In conclusion, the experimental evidence suggests that celecoxib exerts its protective effects in a COX-independent manner.

PMID: 22211872 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Phosphorylation of histone H3 serine 10 in early mouse embryos: active phosphorylation at late S phase and differential effects of ZM447439 on first two embryonic mitoses.

Phosphorylation of histone H3 serine 10 in early mouse embryos: active phosphorylation at late S phase and differential effects of ZM447439 on first two embryonic mitoses.

Cell Cycle. 2010 Dec 1;9(23):4674-87

Authors: Teperek-Tkacz M, Meglicki M, Pasternak M, Kubiak JZ, Borsuk E

Abstract
Cell division in mammalian cells is regulated by Aurora kinases. The activity of Aurora A is indispensable for correct function of centrosomes and proper spindle formation, while Aurora B for chromosome biorientation and separation. Aurora B is also responsible for the phosphorylation of histone H3 serine 10 (H3S10Ph) from G2 to metaphase. Data concerning the Aurora B activity and H3S10Ph in embryonic cells are limited to primordial and maturing oocytes and advanced pronuclei in zygotes. In the present study we have analyzed H3S10Ph in 1- and 2-cell mouse embryos. We show that H3S10 remains phosphorylated at anaphase and telophase of the second meiotic division, as well as during the anaphase and telophase of the first and second embryonic mitoses. At late G1 H3S10 is dephosphorylated and subsequently phosphorylated de novo at late S phase of the first and second cell cycle. These results show that the H3S10 phosphorylation/dephosphorylation cycle in embryonic cells is different than in somatic cells. The behaviour of thymocyte G0 nuclei introduced into ovulated oocytes and early 1-cell parthenogenotes confirms that kinases responsible for de novo H3S10 phosphorylation, most probably Aurora B,� are active until G1 of the first cell cycle of mouse embryo. The inhibition of Aurora kinases by ZM447439 caused abnormalities both in the first and second mitoses. However, the disturbances in each division differed, suggesting important differences in the control of these mitoses. In ZM447439-treated mitotic zygotes Mad2 protein remained continuously present on kinetochores, what confirmed that spindle checkpoint remained active.

PMID: 21099354 [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

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]

dna-pk coxinhibitors c-met inhibitors

2012年11月7日星期三

Histone post-translational modification: from discovery to the clinic.

Histone post-translational modification: from discovery to the clinic.

IDrugs. 2006 Jun;9(6):398-401

Authors: Thomas NR

PMID: 16752306 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Everolimus in metastatic renal cell carcinoma: preliminary experience from chang gung memorial hospital.

Everolimus in metastatic renal cell carcinoma: preliminary experience from chang gung memorial hospital.

Chang Gung Med J. 2012 Sep;35(5):402-7

Authors: Huang WK, Liaw CC, Pang ST, Chuang CK, Chiang YJ, Wu CT, Chang YH, Wang HM, Lin YC, Hsieh JJ, Ou LY, Tsai SI, Yang CH, Yang CT, Chang JW

Abstract
Background: Everolimus has been approved for second-line treatment of patients with metastatic renal cell carcinoma (mRCC) after failure of sorafenib or sunitinib. The purpose of this retrospective study was to assess the efficacy and safety of everolimus in Taiwanese patients with mRCC. Methods: Between March 2009 and August 2011, 24 mRCC patients treated with everolimus were analyzed. Prior to everolimus, each patient had received therapy with at least one vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Progression-free survival (PFS) and overall survival (OS) were estimated according to the Kaplan-Meier method. Results: Fifteen patients (62.5%) achieved stable disease. The median PFS was 7.1 months (95% confidence interval, 3.6-10.5 months). The median OS was 20.7 months (95% confidence interval, 5.0-36.4 months). The most frequent non-hematologic adverse events with everolimus were mucositis, rash, epistaxis and pneumonitis. Conclusions: Everolimus is an effective second-line treatment for Taiwanese patients with mRCC. The toxicity is tolerable and manageable.

PMID: 23127345 [PubMed - in process]

ecdysone chir-258 dovitinib

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]

coxinhibitors c-met inhibitors zm-447439

2012年11月6日星期二

Aurora kinase B, epigenetic state of centromeric heterochromatin and chiasma resolution in oocytes.

Aurora kinase B, epigenetic state of centromeric heterochromatin and chiasma resolution in oocytes.

Reprod Biomed Online. 2009 Sep;19(3):352-68

Authors: Vogt E, Kipp A, Eichenlaub-Ritter U

Abstract
Aurora kinases comprise a family of phosphoproteins performing multiple functions in mitosis and meiosis. Because Aurora kinase B (AURKB) expression is altered in aged oocytes and there is only limited information on its function in meiosis, it was decided to study the spatial distribution and co-localization of AURKB with other regulatory proteins at centromeres during mouse oocyte maturation. AURKB associates with chromosomes after germinal vesicle breakdown, is enriched at centromeres from prometaphase I and transits to the spindle midzone at late anaphase I. Preferential inhibition of AURKB by low concentrations of ZM 447439 inhibitor prevents polar body formation and affects spindle formation and chromosome congression at meiosis I, associated with expression of BubR1 checkpoint protein at kinetochores. Release of cohesion between sister chromatids appears inhibited resulting in failure of chiasma resolution in oocytes progressing to anaphase I. Concomitantly, the inhibitor reduces histone H3 lysine 9 trimethylation at centromeric heterochromatin and affects chromosome condensation. The cytokinesis arrest protects young, healthy oocytes from errors in chromosome segregation although increasing polyploidy. This study shows that changes in activity of AURKB may increase risks for chromosome non-disjunction and aneuploidy in mammalian oocytes, irrespective of age.

PMID: 19778480 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

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

Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase.

Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase.

FEBS Lett. 2005 Jun 20;579(16):3385-91

Authors: Yang H, Burke T, Dempsey J, Diaz B, Collins E, Toth J, Beckmann R, Ye X

PMID: 15922328 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Geminin overexpression induces mammary tumors via suppressing cytokinesis.

Geminin overexpression induces mammary tumors via suppressing cytokinesis.

Oncotarget. 2011 Dec;2(12):1011-27

Authors: Blanchard Z, Malik R, Mullins N, Maric C, Luk H, Horio D, Hernandez B, Killeen J, Elshamy WM

PMID: 22184288 [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

PMID: 17541033 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

2012年11月5日星期一

Aurora B is required for mitotic chromatin-induced phosphorylation of Op18/Stathmin.

Aurora B is required for mitotic chromatin-induced phosphorylation of Op18/Stathmin.

Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4493-8

Authors: Gadea BB, Ruderman JV

PMID: 16537398 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

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

PMID: 18843200 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

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

PMID: 18563426 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

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

PMID: 18843200 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways.

Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways.

Biochem Pharmacol. 2010 Jan 15;79(2):122-9

Authors: Li M, Jung A, Ganswindt U, Marini P, Friedl A, Daniel PT, Lauber K, Jendrossek V, Belka C

Abstract
ZM447439 (ZM) is a potent and selective inhibitor of aurora-A and -B kinase with putative anti-tumoral activity. Inhibitors of aurora kinases were shown to induce apoptosis in vitro and in vivo. To investigate the underlying mechanisms, cell death pathways triggered by ZM was analysed in HCT-116 colorectal cancer cells. Through correlation of polyploidization and apoptosis in different knockout cells, the interrelation of these cellular responses to ZM was investigated. ZM induced apoptosis in a concentration- and time-dependent manner. ZM-induced apoptosis was associated with an upregulation of p53, breakdown of the mitochondrial membrane potential (DeltaPsim) and activation of caspase-3. To precisely define key components for ZM-induced apoptosis, knockout cells lacking p53, Bak, Bax or both Bak and Bax were used. Lack of p53 reduced ZM-induced apoptosis and breakdown of DeltaPsim, while lack of Bak, Bax or both almost completely inhibited apoptosis and breakdown of DeltaPsim. Since no difference in apoptosis induction was detectable between HCT-116 cells lacking Bak, Bax or both, apoptosis induction depended non-redundantly on both Bak and Bax. Phenomenally, ZM induced notable polyploidization in all examined cells, especially in p53-/- cells. A correlation between polyploidization and apoptosis was observed in wild-type, and also in p53-/- cells, albeit with a modest extent of apoptosis. Moreover, in Bak-/-, Bax-/- and Bak/Bax-/- cells apoptosis was totally inhibited in spite of the strongest polyploidization, suggesting apoptosis may be a secondary event following polyploidization in HCT-116 cells. Thus ZM-induced apoptosis depends not only on polyploidization, but also on the intracellular apoptotic signaling.

PMID: 19686703 [PubMed - indexed for MEDLINE]

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2012年11月4日星期日

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]

chir-258 dovitinib dna-pk

Geminin overexpression induces mammary tumors via suppressing cytokinesis.

Geminin overexpression induces mammary tumors via suppressing cytokinesis.

Oncotarget. 2011 Dec;2(12):1011-27

Authors: Blanchard Z, Malik R, Mullins N, Maric C, Luk H, Horio D, Hernandez B, Killeen J, Elshamy WM

PMID: 22184288 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Histone post-translational modification: from discovery to the clinic.

Histone post-translational modification: from discovery to the clinic.

IDrugs. 2006 Jun;9(6):398-401

Authors: Thomas NR

PMID: 16752306 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors

Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.

Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.

Nat Cell Biol. 2011 Oct;13(10):1265-71

Authors: Foley EA, Maldonado M, Kapoor TM

Abstract
Error-free chromosome segregation depends on the precise regulation of phosphorylation to stabilize kinetochore-microtubule attachments (K-fibres) on sister chromatids that have attached to opposite spindle poles (bi-oriented). In many instances, phosphorylation correlates with K-fibre destabilization. Consistent with this, multiple kinases, including Aurora B and Plk1, are enriched at kinetochores of mal-oriented chromosomes when compared with bi-oriented chromosomes, which have stable attachments. Paradoxically, however, these kinases also target to prometaphase chromosomes that have not yet established spindle attachments and it is therefore unclear how kinetochore-microtubule interactions can be stabilized when kinase levels are high. Here we show that the generation of stable K-fibres depends on the B56-PP2A phosphatase, which is enriched at centromeres/kinetochores of unattached chromosomes. When B56-PP2A is depleted, K-fibres are destabilized and chromosomes fail to align at the spindle equator. Strikingly, B56-PP2A depletion increases the level of phosphorylation of Aurora B and Plk1 kinetochore substrates as well as Plk1 recruitment to kinetochores. Consistent with increased substrate phosphorylation, we find that chemical inhibition of Aurora or Plk1 restores K-fibres in B56-PP2A-depleted cells. Our findings reveal that PP2A, an essential tumour suppressor, tunes the balance of phosphorylation to promote chromosome-spindle interactions during cell division.

PMID: 21874008 [PubMed - indexed for MEDLINE]

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