scholarly journals Viability fingerprint of glioblastoma cell lines: roles of mitotic, proliferative, and epigenetic targets

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Darja Lavogina ◽  
Tõnis Laasfeld ◽  
Markus Vardja ◽  
Helen Lust ◽  
Jana Jaal
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Aurora Kinase ◽  
Cell Number ◽  
Treatment Regimes ◽  
Aurora Kinase Inhibitors ◽  
Chemotherapy Agents

AbstractDespite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.

Targeting Aurora Kinases as Therapy in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3484-3484
Author(s):  
Yijiang Shi ◽  
Tony Reiman ◽  
Weiqun Li ◽  
Christopher Maxwell ◽  
Linda Pilarski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Genetic Instability ◽  
Kinase Inhibitors ◽  
Aurora Kinase ◽  
Cell Cycle Checkpoints ◽  
Normal Peripheral Blood ◽  
Aurora Kinases ◽  
Over Expression ◽  
Aurora Kinase Inhibitors

Abstract The aurora kinases A and B are critical for facilitating cell cycle transit from G2 through to cytokinesis. As important regulators of the mitotic event, they are being tested as potential targets in cancer therapy. Multiple myeloma (MM) is a B cell malignancy characterized by progressive genetic instability, suggesting a disruption of cell cycle checkpoints has occurred that normally arrest cells at G2M or within mitosis when injury to the mitotic machinery occurs. Since these deficient checkpoints would prevent cell cycle arrest and potential repair and may render MM cells susceptible to apoptotic death in mitosis, we tested the anti-myeloma effecy of two separate agents that inhibit aurora kinases. Both agents induced cytoreduction of MM cell lines and primary myeloma samples at nM concentrations while normal peripheral blood lymphocytes and CLL cells were not affected. MM cells were not protected by IL-6 or activating mutations of RAS. Anti-myeloma effects were characterized by induction of tetraploidy followed by apoptosis. The myeloma apoptotic effect correlated well with the inhibition of aurora kinase activity as shown by reduction of histone 3B phosphorylation (substrate of auroras). Furthermore, stable ectopic over-expression of aurora kinase A significantly protected MM cells against aurora inhibitors but had no effect on apoptosis induced by velcade. As expression of the centrosomal protein RHAMM in MM cells may contribute to genetic instability, we tested effects of RHAMM over-expression on the sensitivity to aurora inhibitors. Although RHAMM over-expression in transfected MM cells was very modest, it significantly enhanced sensitivity to apoptosis induced by aurora kinase inhibitors. These results suggest the potential for aurora kinase inhibitors in multiple myeloma especially in patients where RHAMM is over-expressed.

Vincristine Potentiates the Anti-Leukemia Effect of the Aurora Kinase Inhibitor VE-465 by Enhancing Apoptosis in Myeloid Leukemia Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2762-2762
Author(s):  
Ken Ohmine ◽  
Tadashi Nagai ◽  
Kozue Yoshida ◽  
Shin-ichiro Fujiwara ◽  
Mitsuyo Uesawa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Leukemia Cells ◽  
Aurora Kinases ◽  
Aurora Kinase Inhibitors ◽  
M Phase ◽  
G1 Cells

Abstract Abstract 2762 Poster Board II-738 Introduction: Aurora kinases (Aurora-A, Aurora-B, Aurora-C) play an essential role in the regulation of mitosis. It has been shown that deregulation of aurora kinases is involved in tumorgenesis and that these kinases are overexpressed in a variety of tumor cells. Aurora kinase inhibitors are potential small-molecule agents for treatment of various kinds of tumors including leukemia, and clinical trials of several aurora kinase inhibitors against certain types of tumors are currently being carried out. However, mono-therapy with other small-molecule agents sometimes shows only limited clinical efficacy for treatment of leukemia, and the establishment of efficacious combination therapies therefore appears to be an attractive approach for making good use of aurora kinase inhibitors. Methods: We examined the cytotoxic effects of VE-465, a specific aurora kinase inhibitor, in combination with various conventional anti-leukemia agents, including doxorubicin, daunorubicin, idarubicin, mitoxantron, cytocine arabinoside, vincristine and etoposide, on AML cell lines (HL60, U937, THP-1, KY821), CML cell lines (KCL22, K562, KU812) and primary leukemia cells from a patient with AML in order to try to determine an effective therapeutic combination. Results: Steel and Peckham isobologram analyses demonstrated that a combination of VE-465 and vincristine had a synergistic/additive inhibitory effect on the growth of all leukemia cell lines as well as primary leukemia cells examined in this study. Flow cytometric analysis showed that the percentage of G2/M-phase cells was significantly increased at 12 h when VE-465 was added to THP-1 cells as a single agent. At 48 h, however, the percentage of sub-G1 cells was increased, with a decrease in the percentage of G2/M-phase cells, suggesting that VE-465 initially induced the cells into blockage of the cell cycle at M-phase, which may be caused by VE-465-mediated inhibition of aurora kinase activity, and that cells at G2/M arrest were subsequently induced to apoptosis. Importantly, vincristine enhanced VE-465-mediated induction of sub-G1 cells. Consistent with these results, vincristine enhanced VE-465-induced increase in the levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9 and cleaved PARP. The level of Phospho-Chk2 was markedly increased by the combination, suggesting that Chk2-mediated activation of the G2/M checkpoint is involved in the induction of apoptosis. Interestingly, VE-465 alone and VE-465 in combination with vincristine markedly increased the level of phospho-ERK1/2, suggesting that the combination alters a network of cellular signaling pathways. Taken together, the results suggest that vincristine potentiated the effect of VE-465 by enhancement of apoptosis, resulting in effective inhibition of the growth of leukemia cells. In contrast to the combination of VE-465 and vincristine, however, combinations of VE-465 and other anti-leukemia agents showed no synergistic inhibition but rather had antagonistic effects on growth. Conclusion: Co-administration of VE-465 and most of the conventional anti-leukemia agents might have little clinical value. However, the results of this study indicate the utility of the combination of VE-465 and vincristine as a potential therapy for myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

Induction of CABLES1 by the TKI Inhibits the Cell Cycle Progression and Induces Apoptosis In CML Cell.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1199-1199
Author(s):  
Tomonari Takemura ◽  
Satoki Nakamura ◽  
Yasuyuki Nagata ◽  
Daisuke Yokota ◽  
Isao Hirano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Cycle Progression ◽  
Abl Kinase ◽  
Abl Kinase Inhibitors

Abstract Abstract 1199 [Background and Aims] CABLES1 (cyclin-dependent kinase (CDK)-5 and ABL enzyme 1) is a regulator of cell proliferation, apoptosis, and cell cycle, and it has been reported to be lost in a variety cancers. It has been also reported that knockout of the Cable1 gene has minimal to no effect on hematopoietic stem cells. However, we found that the expression of Cables1 gene and CABLES1 protein was suppressed in CML cells, and its function is little known in CML. In this study, we have investigated the function of CABLES1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of Cables1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p53 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Cables1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with Cables1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of Cables1 mRNA and CABLES1 protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells transfected with the Cables1 cDNA, it is shown that CML cell proliferation was inhibited, and the phosphorylation levels of p53, and the expression of BAX and p21 protein were markedly increased compared to the untransfected cells. In addition, the overexpression of CABLES1 induced G1 cell cycle arrest and reduced the DiOC6 fluorescence, indicating breakdown of the mitochondrial membrane potential in CML cells. On the other hand, the changes of p73 and p27 protein expression were not detected. Moreover, in CML cells transfected with Cables1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of Cables1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of Cables1 mRNA and CABLES1 protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of CABLES1, and the depletion of CABLES1 promotes cell cycle progression and p53-dependent apoptosis. Moreover, the induction of CABLES1 expression has the potentiality to eradicate CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals 47 Preclinical studies of dianhydrogalactitol (VAL-083) in DIPG, as single agent or as a combination with AZD1775 or radiation

2018 ◽  
Vol 45 (S3) ◽  
pp. S9-S10
Author(s):  
Xiaodong Yang ◽  
Anne Steino ◽  
Jeffrey Bacha ◽  
Dennis Brown ◽  
Sabine Mueller
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Cell Cycle Progression ◽  
Single Agent ◽  
Chemotherapeutic Agents ◽  
Phase Cell ◽  
Dna Double Strand Breaks

Despite decades of trials, the prognosis for diffuse intrinsic pontine gliomas (DIPG) remains dismal. DIPG is inoperable and standard treatment is radiation alone, as the addition of chemotherapeutic agents, such as temozolomide, have not improved survival. In addition to inherent chemoresistance, treatment of DIPG is impeded by an intact blood-brain barrier (BBB). VAL-083 is a structurally unique bi-functional DNA-targeting agent that readily crosses the BBB. VAL-083 forms interstrand DNA crosslinks at N7-guanine, resulting in DNA double-strand breaks (DSB), S/G2-phase cell-cycle arrest, and ultimately cancer cell death. We have previously demonstrated that VAL-083 is able to overcome temozolomide-resistance in vitro and in vivo, and that its cytotoxicity is independent of the DNA-repair enzyme O6-methylguanine DNA-methyltransferase (MGMT). MGMT is almost universally expressed in DIPG and its expression is strongly correlated with temozolomide-resistance. VAL-083’s distinct mechanism-of-action suggests the potential for combination with inhibitors of DNA DSB repair or S/G2 cell-cycle progression (e.g. Wee1 inhibitor AZD1775). Here, we investigated the effects of VAL-083 in combination with radiation, AZD1775 or irinotecan (topoisomerase inhibitor) in three DIPG cell-lines: SF10693 (H3.1), SF8628 (H3.3) and NEM157 (H3.3). VAL-083 showed activity at low uM-concentration in all three cell-lines. In addition, VAL-083 showed synergy with AZD1775 in all three cell-lines. Combined with its ability to cross the BBB, accumulate in brain tumor tissue and overcome MGMT-related chemoresistance, these results suggest VAL-083 as a potentially attractive treatment option for DIPG as single agent or in combination with AZD1775. Combination studies with radiation are ongoing and will be presented at the meeting.

scholarly journals Epigenetic Drug Screen on Resistant CLL Cells Reveals Aurora Kinase Inhibitors As Enhancers of CD20 Expression and Sensitizers to Treatment with CD20 Monoclonal Antibodies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4407-4407
Author(s):  
Veronika Kozlova ◽  
Aneta Ledererova ◽  
Michael Doubek ◽  
Jiri Mayer ◽  
Sarka Pospisilova ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Lines ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Aurora Kinase ◽  
Epigenetic Drugs ◽  
Aurora Kinase Inhibitors ◽  
Epigenetic Drug ◽  
Cd20 Expression ◽  
Resistant Cells

Abstract Background: Chronic lymphocytic leukemia (CLL) still remains an incurable disease. In spite of tremendous success of some targeted agents, the main mode of therapy in routine practice relies on the application of CD20 monoclonal antibodies (mAbs). Yet, majority of patients relapses and fails the immunotherapy, the major reason presumably being low expression of CD20 target protein on the surface of malignant cells. Whereas the molecular mechanisms regulating CD20 are largely unknown, the possibility to modulate CD20 levels seems an appealing strategy to enhance the success rate of CD20 immunotherapy. Aim: We aimed to screen epigenetic drug library on our generated immunotherapy-resistant CLL cell lines in order to reveal drugs able to upregulate CD20 expression and thereby sensitize cells to further CD20-mAb treatment. Methods: Through chronic cell exposure to gradually increasing doses of CD20 mAbs we have generated cells permanently resistant to anti-CD20 immunotherapy. These cells have strongly reduced CD20 expression. Epigenetic drug library (182 drugs) was applied on such cells in triplicates at 10uM concentration for 72 hours and changes in CD20 expression were determined by flow cytometry. Viability of the cells treated with epigenetic drugs in combination with CD20 mAb was measured by a CellTiter-Glo assay. Results: Screening the library of 182 epigenetic drugs on immunotherapy-resistant CD20-low cells revealed multiple drugs that were able to upregulate CD20 expression more than 2-fold. Among these were significantly enriched multiple inhibitors of Aurora kinases (AURK). In fact, there were 12 diverse Aurora kinase inhibitors among the top 16 hits. In parallel, we performed another epigenetic screen on our resistant cells, combining the epigenetic drugs with the addition of CD20-mAb Rituximab (RTX) to search for drugs able to sensitize cells to RTX treatment. Aurora kinase inhibitors were again found among the top three groups of strongest immunotherapy sensitizers. We could then validate several selected AURK inhibitors in individual experiments and showed that the upregulation of CD20 was concentration dependent. Importantly, we did not observe any induction of CD20 in non-B cell lines upon AURK inhibitor treatment. On contrary, we found that AURK inhibitors triggered marked increase in CD20 in cell lines resistant to both RTX and also to another CD20 mAb Ofatumumab, whereas they had only minor effect upon wildtype cells. The increase in CD20 was sustained for extended time periods. Pretreating resistant cells with AURK inhibitors followed by RTX treatment induced a profound shift in the viability curve, leading to a 50-fold improvement in EC50 for RTX as compared to cells without pretreatment. Conclusion: Aurora kinase inhibitors are able to specifically and strongly enhance expression of CD20 antigen on the surface of immunotherapy-resistant cells and thereby they strongly sensitize cells to further treatment with CD20 mAbs. These inhibitors thus seem as suitable candidates for combination therapy together with CD20 antibodies. This research has been financially supported by the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601) and by the research grant AZV-MZ-CR 15-33561AA-4/2015 and grant MUNI/A/0968/2017. Disclosures Doubek: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Affimed: Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy. Mayer:Eisai: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Roche: Research Funding; Affimed: Research Funding.

Targeting Aurora Kinases in Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4907-4907
Author(s):  
Ya-Ping Chen ◽  
Hui-Ju Lin ◽  
Kung-Chao Chang ◽  
Jiann-Shiuh Chen ◽  
Ming-Ying Tsai ◽  
...  
Keyword(s):  
Cell Lines ◽  
Drug Sensitivity ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Aurora Kinase ◽  
Drug Resistant ◽  
Rt Pcr ◽  
Aurora Kinases ◽  
Aurora Kinase Inhibitors ◽  
Mdr 1

Abstract Abstract 4907 Introduction: Despite improved treatment outcome in acute lymphoblastic leukemia (ALL), drug resistance and disease recurrence remain major obstacles in specific subgroups. Thus, there is an urgent need to identify new targets for therapy. Several studies showed that Aurora kinases were therapeutic targets in cancer therapy, including solid tumors and hematological malignancies. Here we describe preclinical testing of Aurora kinase inhibitors in ALL and the molecular mechanism of different drug activity. Materials and methods: Quantitative RT-PCR and Western blot were used to assess the expressions of Aurora kinases and their activators in ALL. RT-PCR was used to detect the expression of MDR-1. To test activity against Aurora kinases, different ALL cell lines were treated with various concentrations of Aurora kinase inhibitors “VE-465 and VX-680”. The effects of Aurora kinase inhibitors on the cell cycle were evaluated by flow cytometry. Gene expression profiling was performed to identify the candidate targets which regulate the different drug sensitivity. Transient knockdown and overexpression of candidate genes in ALL cell lines were also employed in this study. Results: Nine ALL cell lines treated with Aurora kinase inhibitors (VE-465 and VX-680) exhibited different drug sensitivity. Five ALL cell lines were sensitive to drug treatment with IC50 around 10–40 nM, including MLL-AF4-positive and BCR-ABL-positive cell lines. However, RPMI-8402 was one of the three cell lines which were resistant to VE-465 and VX-680 with IC50 more than 10 μM. Among these sensitive ALL cell lines, treatment of Aurora kinase inhibitors resulted in an increased G2/M and sub-G1 populations. In contrast, drug-resistant ALL cell lines showed increased polyploidy status after exposure to Aurora kinase inhibitors. The different treatment efficacy was not related to the expression of Aurora kinases, their activators or MDR-1. In order to elucidate the molecular mechanism to regulate the different drug sensitivity, microarray study was performed. It showed that treatment of Aurora kinase inhibitors resulted in differential expressions of genes (75 up-regulated and 90 down-regulated genes) and CDKN1Awas one of the potential molecules which regulated the treatment diversity. RT-PCR and Western blot confirmed the cDNA microarray data: CDKN1A was up-regulated after treatment with Aurora kinase inhibitors in the drug-sensitive cell lines, but no change in the level of CDKN1A in the drug-resistance cell lines. Knockdown of CDKN1A in drug-sensitive cell lines impaired the treatment activity. Over-expression of CDKN1A in drug-resistant cell lines increased the anti-leukemia effect of Aurora kinase inhibitors. Conclusion: These data suggest that treatment with Aurora kinase inhibitors may be a novel and effective therapy in specific subgroups of ALL, including MLL-AF4-positive ALL. These data show that status of Aurora kinases, their activators or MDR-1 does not correlate with the drug susceptibility in ALL cell lines. The susceptibility to Aurora kinase inhibitors in ALL depends on the activation status of CDKN1A. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1135
Author(s):  
David Howard ◽  
David James ◽  
Kate Murphy ◽  
Jezabel Garcia-Parra ◽  
Belen Pan-Castillo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Endometrial Cancer ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Type I ◽  
Cycle Progression ◽  
Carboxy Terminal

Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II–IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.

scholarly journals TReP-132 Controls Cell Proliferation by Regulating the Expression of the Cyclin-Dependent Kinase Inhibitors p21WAF1/Cip1 and p27Kip1

2005 ◽  
Vol 25 (11) ◽  
pp. 4335-4348 ◽  
Author(s):  
Florence Gizard ◽  
Romain Robillard ◽  
Olivier Barbier ◽  
Brigitte Quatannens ◽  
Anne Faucompré ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Mrna Levels ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
P27 Gene

ABSTRACT The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RNA resulted in increased G1→S cell cycle progression. The growth-inhibitory effects of TReP-132 was further shown to be mediated by induction of G1 cyclin-dependent kinase inhibitors p21WAF1 (p21) and p27KIP1 (p27) expression levels. As a consequence, G1 cyclin/cyclin-dependent kinase activities and pRB phosphorylation were markedly reduced, and cell cycle progression was blocked in the G1 phase. The stimulatory effect of TReP-132 on p21 and p27 gene transcription involved interaction of TReP-132 with the transcription factor Sp1 at proximal Sp1-binding sites in their promoters. Moreover, in different breast tumor cell lines, endogenous TReP-132 expression was positively related with a lower proliferation rate. In addition, TReP-132 knockdown resulted in enhanced cell proliferation and lowered p21 and p27 mRNA levels in the steroid-responsive and nonresponsive T-47D and MDA-MB-231 cell lines, respectively. Finally, a statistic profiling of human breast tumor samples highlighted that expression of TReP-132 is correlated with p21 and p27 levels and is associated with lower tumor incidence and aggressiveness. Together, these results identify TReP-132 as a basal cell cycle regulatory protein acting, at least in part, by interacting with Sp1 to activate the p21 and p27 gene promoters.

Aurora Kinase Inhibitors in Head and Neck Cancer

2018 ◽  
Vol 18 (3) ◽  
pp. 199-213
Author(s):  
Guangying Qi ◽  
Jing Liu ◽  
Sisi Mi ◽  
Takaaki Tsunematsu ◽  
Shengjian Jin ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Cancer Therapy ◽  
Kinase Inhibitors ◽  
Biological Function ◽  
Aurora Kinase ◽  
Aurora Kinases ◽  
Related Research ◽  
Chemotherapy Drugs ◽  
Aurora Kinase Inhibitors

Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represent a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.

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