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1.
G. E. Morozevich N. I. Kozlova O. Y. Susova A. Y. Lupatov A. E. Berman 《Biochemistry. Biokhimii?a》2017,82(9):1017-1024
In MCF-7 human breast carcinoma cells, α5β1 integrin hyperexpression, which was accomplished by transduction of a full-length α5 integrin cDNA, increased by about 50-70% the number of cells, survived during 48-72 h cell treatment with doxorubicin. Up-regulation of α5β1 reduced the level of the apoptogenic p53 protein and p21 cell cycle inhibitor, but enhanced the activity of Akt and mTOR protein kinases. In addition to these findings, we observed a significant decrease in the activity of both isoforms of phosphokinase Erk1/2, which is known to play a key role in cell viability pathways, including pathways alleviating stress damages caused by distinct antitumor drugs. Diminished Erk activity accompanying the rise of drug resistance can be explained by an “atypical” function of this kinase, which, in the cells studied, promotes an enhanced rather than reduced sensitivity to doxorubicin. To verify this suggestion, the effect of a specific Erk inhibitor, PD98059, on the resistance to doxorubicin of control and α5 cDNA-transduced MCF-7 cells was investigated. The data showed that suppression of Erk activity increased the resistance of control cells (transduced with an “empty” vector) to a level higher than that demonstrated by the α5 cDNA-transduced cells. The highest level of resistance was observed in α5β1trancduced cells treated with PD98059. Akt and mTOR kinase inhibitors had little if any effect on doxorubicin resistance of α5 cDNA-transduced MCF-7 cells. The data show for the first time that integrin α5β1 can stimulate drug resistance of tumor cells through a mechanism based on the inhibition of protein kinase Erk. From a more general view, the results of this investigation suggest that signal protein kinases can perform in tumor cells “non-canonical” functions, opposite to those, which are the basis for using kinase inhibitors in targeted cancer therapy. It follows that if a protein kinase is supposed to be used as a target for such therapy, it is important to explore its features in the particular tumor prior to the onset of treatment. 相似文献
2.
Ye Seul Kim Seong-Hoon Kim Joon Shin Amaravadhi Harikishore Jong-Kwan Lim Youngseob Jung Ha-Na Lyu Nam-In Baek Kwan Yong Choi Ho Sup Yoon Kyong-Tai Kim 《PloS one》2014,9(10)
Uncontrolled proliferation, a major feature of cancer cells, is often triggered by the malfunction of cell cycle regulators such as protein kinases. Recently, cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, because they play fundamental roles in cellular proliferation. However, the protein kinase-targeted drugs that have been developed so far do not show impressive clinical results and also display severe side effects; therefore, there is undoubtedly a need to investigate new drugs targeting other protein kinases that are critical in cell cycle progression. Vaccinia-related kinase 1 (VRK1) is a mitotic kinase that functions in cell cycle regulation by phosphorylating cell cycle-related substrates such as barrier-to-autointegration factor (BAF), histone H3, and the cAMP response element (CRE)-binding protein (CREB). In our study, we identified luteolin as the inhibitor of VRK1 by screening a small-molecule natural compound library. Here, we evaluated the efficacy of luteolin as a VRK1-targeted inhibitor for developing an effective anti-cancer strategy. We confirmed that luteolin significantly reduces VRK1-mediated phosphorylation of the cell cycle-related substrates BAF and histone H3, and directly interacts with the catalytic domain of VRK1. In addition, luteolin regulates cell cycle progression by modulating VRK1 activity, leading to the suppression of cancer cell proliferation and the induction of apoptosis. Therefore, our study suggests that luteolin-induced VRK1 inhibition may contribute to establish a novel cell cycle-targeted strategy for anti-cancer therapy. 相似文献
3.
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD). Selective chemical inhibitors of the PBD would constitute tools to probe for PBD-dependent functions of Plk1 and could be advantageous in cancer therapy. The discovery of Poloxin and thymoquinone as PBD inhibitors indicated that small, cell-permeable chemical inhibitors could be identified. Other efforts followed, including ours, reporting additional molecules capable of blocking the PBD. It is now clear that, unfortunately, most of these compounds are non-specific protein alkylators (defined here as groups covalently added via a carbon) that have little or no potential for the development of real Plk1 PBD-specific drugs. This situation should be minded by biologists potentially interested in using these compounds to study Plk1. Further efforts are needed to develop selective, cell-permeable PBD inhibitors. 相似文献
4.
WEE1激酶是一种细胞周期调节蛋白,能调控细胞周期蛋白依赖性激酶1(cyclin-dependent kinase 1,CDK1)的磷酸化状态,从而调节CDK1与细胞周期蛋白B(cyclin B)复合物的活性从而实现对细胞周期的调控,且对DNA损伤检查点具有重要的调节作用。WEE1是G2/M期阻滞的关键基因,起着重要的监测作用,在一些癌症中过表达,抑制或下调WEE1激酶均能引发有丝分裂灾难,因此WEE1激酶抑制剂可能在抗癌治疗中有关键作用。在癌症的治疗过程中,WEE1抑制剂与DNA损伤剂、化学药物等联合使用会得到比单独使用更为有效,且在p53缺失的癌细胞中能发挥更好的效果。目前WEE1已成为许多癌症治疗的关键靶点之一,其抑制剂MK-1775已处于临床研究阶段,且能增强一些DNA损伤剂对p53缺失的癌细胞的杀伤能力。本文就WEE1激酶及其抑制剂在抗癌治疗中的应用作一综述。 相似文献
5.
Dr. Salwa Magdy Eldaly Dalia Salama Zakaria Prof. Dr. Nadia Hanafy Metwally 《化学与生物多样性》2023,20(10):e202300138
Synthesis of new anticancer candidates with protein kinases inhibitory potency is a major goal of pharmaceutical science and synthetic research. This current work represents the synthesis of a series of substituted benzoate-thiazolidinones. Most prepared thiazolidinones were evaluated in vitro for their potential anticancer activity against three cell lines by MTT assay, and they found to be more effective against cancer cell lines with no harm toward normal cells. Thiazolidinones 5 c and 5 h were further evaluated to be kinase inhibitors against EGFR showing effective inhibitory impact (with IC50 value; 0.2±0.009 and 0.098±0.004 μM, for 5 c and 5 h , respectively). Furthermore, 5 c and 5 h have effects on cell cycle and apoptosis induction capability in HepG2 cell lines by DNA-flow cytometry analysis and annexin V-FITC apoptosis assay, respectively. The results showed that they have effect of disrupting the cell cycle and causing cell mortality by apoptosis in the treated cells. Moreover, molecular docking studies showed better binding patterns for 5 c and 5 h with the active site of the epidermal growth factor receptor (EGFR) protein kinase (PDB code 1M17). Finally, toxicity risk and physicochemical characterization by Osiris method was performed on most of the compounds, revealing excellent properties as possible drugs. 相似文献
6.
Hormone-induced intercellular signal transfer dissociates cyclic AMP- dependent protein kinase 总被引:3,自引:1,他引:2
We used co-cultures of porcine ovarian granulosa cells and mouse adrenocortical tumor cells (Y-1) to examine the kinetics of contact-dependent intercellular signal transfer and to assess the molecular mechanisms employed by this process. Exposure to follicle-stimulating hormone (FSH) caused cAMP-dependent protein kinase dissociation in granulosa cells and, with time, in Y-1 cells if, and only if, they contacted a responding granulosa cell. Y-1 cells close to a granulosa cell but not touching it failed to respond similarly. In reciprocal experiments, co-cultures were stimulated with adrenocorticotropic hormone (ACTH). Y-1 cells dissociated protein kinase as did granulosa cells in contact with Y-1 cells; however, granulosa cells that were not in contact with Y-1 cells failed to respond to the hormone. Fluorogenic steroids were secreted by Y-1 cells cultured alone and stimulated with ACTH, but were not secreted by cultures exposed to FSH. Neither hormone caused fluorogenic steroid production by granulosa cells. On the other hand these steroids were secreted in co-cultures stimulated with ACTH and to a lesser degree in co-cultures exposed to FSH. Autoradiography revealed that I125-FSH bound only to granulosa cells, never to Y-1 cells, even if they were in contact with an ovarian cell. The possibility of cell fusion was tested by experiments in which Y-1 cell membranes were labeled with cationized ferritin. These cells were then placed in co-culture with ovarian granulosa cells that had previously been allowed to ingest latex spheres. At regions of gap junctions between Y-1 and granulosa cells ferritin remained attached to the adrenal cell membrane and was never observed to migrate to the granulosa cell membrane. From these data, we conclude that hormone specific stimulation of one cell type leads to protein kinase dissociation in heterotypic partners only if they contact a hormone responsive cell. This signal transfer is bidirectional, exhibits temporal kinetics and occurs in the absence of apparent cell fusion. The only structural feature connecting Y-1 and granulosa cells were gap junctions implying they provided the communication channels; however, alternative mechanisms cannot be excluded. We have not established the identity of the signal being transferred although cAMP is a logical candidate. 相似文献
7.
Bruno Chauffert Marie-Thérèse Dimanche-Boitrel Carmen Garrido Mikael Ivarsson Monique Martin François Martin Eric Solary 《Cytotechnology》1998,27(1-3):225-235
Kinetic resistance plays a major role in the failure of chemotherapy towards many solid tumors. Kinetic resistance to cytotoxic
drugs can be reproduced in vitro by growing the cells as multicellular spheroids (Multicellular Resistance) or as hyperconfluent
cultures (Confluence-Dependent Resistance). Recent findings on the cell cycle regulation have permitted a better understanding
why cancer cells which arrest in long quiescent phases are poorly sensitive to cell-cycle specific anticancer drugs. Two cyclin-dependent
kinase inhibitors (CDKI) seem particularly involved in the cell cycle arrest at the G1 to S transition checkpoint: the p53-dependent
p21cip1 protein which is activated by DNA damage and the p27kip1 which is a mediator of the contact inhibition signal. Cell quiescence could alter drug-induced apoptosis which is partly
dependent on an active progression in the cell cycle and which is facilitated by overexpression of oncogenes such as c-Myc
or cyclins. Investigations are yet necessary to determine the influence of the cell cycle on the balance between antagonizing
(bcl-2, bcl-XL...) or stimulating (Bax, Bcl-XS, Fas...) factors in chemotherapy-induced apoptosis. Quiescent cells could also be protected from toxic agents by an enhanced
expression of stress proteins, such as HSP27 which is induced by confluence. New strategies are required to circumvent kinetic
resistance of solid tumors: adequate choice of anticancer agents whose activity is not altered by quiescence (radiation, cisplatin),
recruitment from G1 to S/G2 phases by cell pretreatment with alkylating drugs or attenuation of CDKI activity by specific
inhibitors.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
8.
蛋白激酶在真核细胞信号转导中起重要作用,影响了生长、发育、迁移以及凋亡等各个细胞过程。其表达水平或活性异常时,就有可能导致癌症、心血管疾病以及其他各种疾病,因此蛋白激酶是治疗这些疾病很好的分子靶点。迄今为止,美国食品药品监督管理局已经批准了28个蛋白激酶的抑制剂作为上市药物,用于相应的临床治疗。目前存在着各种检测激酶活性的方法,激酶生化检测方法尤为众多,比较经典的有放射性同位素的方法,也有一些非均相非放射性同位素的方法,诸如酶联免疫法、反相高效液相色谱法、核磁共振分析法等等。而各种均相非放射性同位素的检测方法,由于其污染小、操作便捷,逐渐成为激酶抑制剂筛选的首选。本文综述了各种激酶生化检测方法及其发展历史,并介绍了一些新的趋势,如激酶酶谱筛选。 相似文献
9.
《Cell cycle (Georgetown, Tex.)》2013,12(12):1414-1417
We have recently shown that all kinds of non-proliferating cells, including quiescent, senescent, and terminally differentiated ones, can be mitotically reactivated by the sole removal of cell type-specific cyclin-dependent kinase inhibitors. Reactivation takes place irrespective of added growth factors, allowing otherwise quiescent or senescent cells to proliferate. These unexpected findings warrant a reappraisal of some key aspects of the cell cycle. Inhibitors do not only modulate kinase activity, but contribute to the decision to enter the cell cycle as much as cyclins themselves. Non-proliferating cells, even those destined never to reenter the cell cycle, continue to express functionally significant levels of preassembled cyclin-cdk complexes, making cell cycle-arrest a state that must be constantly maintained by active expression of cyclin-dependent kinase inhibitors (CKIs). In addition, we suggest that the novel findings can be exploited in human therapy to accelerate, promote, or induce cell proliferation, both in vitro and in vivo. They should prove advantageous in cell biotechnology, cell replacement therapy, and tissue repair, wherever cell proliferation constitutes a limiting factor. 相似文献
10.
Polo-like kinase I (PLK1), a cell cycle regulating kinase, has been shown to have oncogenic function in several cancers. Although PLK1 inhibitors, such as BI2536, BI6727 (volasertib) and NMS-1286937 (onvansertib) are generally well-tolerated with a favorable pharmacokinetic profile, clinical successes are limited due to partial responses in cancer patients, especially those in advanced stages. Recently, combination therapies targeting multiple pathways are being tested for cancer management. In this review, we first discuss structure and function of PLK1, role of PLK1 in cancers, PLK1 specific inhibitors, and advantages of using combination therapy versus monotherapy followed by a critical account on PLK1-based combination therapies in cancer treatments, especially highlighting recent advancements and challenges. PLK1 inhibitors in combination with chemotherapy drugs and targeted small molecules have shown superior effects against cancer both in vitro and in vivo. PLK1-based combination therapies have shown increased apoptosis, disrupted cell cycle, and potential to overcome resistance in cancer cells/tissues over monotherapies. Further, with successes in preclinical experiments, researchers are validating such approaches in clinical trials. Although PLK1-based combination therapies have achieved initial success in clinical studies, there are examples where they have failed to improve patient survival. Therefore, further research is needed to identify and validate novel biologically informed co-targets for PLK1-based combinatorial therapies. Employing a network-based analysis, we identified potential PLK1 co-targets that could be examined further. In addition, understanding the mechanisms of synergism between PLK1 inhibitors and other agents may lead to a better approach on which agents to pair with PLK1 inhibition for optimum cancer treatment. 相似文献
11.
Neckers L 《Journal of biosciences》2007,32(3):517-530
Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally
activated and/or expressed signalling proteins, as well as multiple mutated, chimeric, and/or over-expressed signalling proteins,
that promote cancer cell growth and/or survival. Hsp90 inhibitors are unique in that, although they are directed towards a
specific molecular target, they simultaneously inhibit multiple cellular signalling pathways. By inhibiting nodal points in
multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic
agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer
cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors,
both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90
inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client proteins are neurotoxic,
these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90
inhibitors in treating multiple pathologies involving neurodegeneration. 相似文献
12.
Kei-ichi Ozaki Nobuyuki Baba Toshiaki Sakamoto Susumu Tanimura 《Biochemical and biophysical research communications》2010,391(4):1610-1615
Deregulated activation of protein tyrosine kinases, such as the epidermal growth factor receptor (EGFR) and Abl, is associated with human cancers including non-small cell lung cancer (NSCLC) and chronic myeloid leukemia (CML). Although inhibitors of such activated kinases have proved to be of therapeutic benefit in individuals with NSCLC or CML, some patients manifest intrinsic or acquired resistance to these drugs. We now show that, whereas blockade of either the extracellular signal-regulated kinase (ERK) pathway or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway alone induced only a low level of cell death, it markedly sensitized NSCLC or CML cells to the induction of apoptosis by histone deacetylase (HDAC) inhibitors. Such enhanced cell death induced by the respective drug combinations was apparent even in NSCLC or CML cells exhibiting resistance to EGFR or Abl tyrosine kinase inhibitors, respectively. Co-administration of a cytostatic signaling pathway inhibitor may contribute to the development of safer anticancer strategies by lowering the required dose of cytotoxic HDAC inhibitors for a variety of cancers. 相似文献
13.
Ghanshyam Teli Rohit Pal Lalmohan Maji Sindhuja Sengupta Nulgumnalli Manjunathaiah Raghavendra Gurubasavaraja Swamy Purawarga Matada 《化学与生物多样性》2023,20(9):e202300515
The physiological Src proto-oncogene is a protein tyrosine kinase receptor that served as the essential signaling pathway in different types of cancer. Src kinase receptor is divided into different domains: a unique domain, an SH3 domain, an SH2 domain, a protein tyrosine kinase domain, and a regulatory tail, which runs from the N-terminus to the C-terminus. Src kinase inhibitors bind in the kinase domain and are activated by phosphorylation. The etiology of cancer involved various signaling pathways and Src signaling pathways are also involved in those clusters. Although the dysregulation of Src kinase resulted in cancer being discovered in the late 19th century it is still considered a cult pathway because it is not much explored by different medicinal chemists and oncologists. The Src kinase regulated through different kinase pathways (MAPK, PI3K/Akt/mTOR, JAK/STAT3, Hippo kinase, PEAK1, and Rho/ROCK pathways) and proceeded downstream signaling to conduct cell proliferation, angiogenesis, migration, invasion, and metastasis of cancer cells. There are numerous FDA-approved drugs flooded the market but still, there is a huge demand for the creation of novel anticancer drugs. As the existing drugs are accompanied by several adverse effects and drug resistance due to rapid mutation in proteins. In this review, we have elaborated about the structure and activation of Src kinase, as well as the development of Src kinase inhibitors. Our group also provided a comprehensive overview of Src inhibitors throughout the last two decades, including their biological activity, structure-activity relationship, and Src kinase selectivity. The Src binding pocket has been investigated in detail to better comprehend the interaction of Src inhibitors with amino acid residues. We have strengthened the literature with our contribution in terms of molecular docking and ADMET studies of top compounds. We hope that the current analysis will be a useful resource for researchers and provide glimpse of direction toward the design and development of more specific, selective, and potent Src kinase inhibitors. 相似文献
14.
Gaben AM Saucier C Bedin M Redeuilh G Mester J 《Molecular endocrinology (Baltimore, Md.)》2004,18(11):2700-2713
15.
BACKGROUND: Our understanding of protein kinase inhibition in the treatment of cancer is clearly limited by the lack of inhibitors that selectively block a single kinase implicated in neoplastic transformation. One approach to developing specific inhibitors is to engineer in protein kinases silent mutations that allow selective inhibition while retaining kinase activity. Because it is implicated in a large number of malignancies, EGFR provides an attractive target for such selective kinase inhibition.RESULTS: We generated an inhibitor-sensitized allele of the transforming receptor tyrosine kinase v-erbB. Transformation of immortalized rodent fibroblasts by sensitized versions of v-erbB (v-erbB-as1) was blocked by 1-napthyl PP1 (NaPP1), a cell-permeable ATP-competitive inhibitor. NaPP1 also reversed morphological transformation by v-erbB-as1. Signaling through MAP kinase and PI(3) kinase was initially blocked by inhibitor treatment and then recovered to levels comparable to those in nontransformed cells. Surprisingly, NaPP1-treated v-erbB-as1 cells failed to re-enter the cell cycle, showed decreased levels of D- and A-type cyclins, and showed increased levels of p27. To extend this result, we showed that NaPP1 treatment of v-Src-as1 cells also led to cell cycle arrest. Arrested cells could be rescued with a conditional allele of Raf or by transduction of a constitutive allele of cyclin D1.CONCLUSIONS: These data suggest that mammalian cells can become dependent on aberrant oncogenic signaling; this dependency renders them incapable of returning to a normal, proliferative phenotype. 相似文献
16.
Garcia HH Brar GA Nguyen DH Bjeldanes LF Firestone GL 《The Journal of biological chemistry》2005,280(10):8756-8764
Indole-3-carbinol (I3C), a dietary compound found in cruciferous vegetables, induces a robust inhibition of CDK2 specific kinase activity as part of a G1 cell cycle arrest of human breast cancer cells. Treatment with I3C causes a significant shift in the size distribution of the CDK2 protein complex from an enzymatically active 90 kDa complex to a larger 200 kDa complex with significantly reduced kinase activity. Co-immunoprecipitations revealed an increased association of both a 50 kDa cyclin E and a 75 kDa cyclin E immunoreactive protein with the CDK2 protein complex under I3C-treated conditions, whereas the 90 kDa CDK2 protein complexes detected in proliferating control cells contain the lower molecular mass forms of cyclin E. I3C treatment caused no change in the level of CDK2 inhibitors (p21, p27) or in the inhibitory phosphorylation states of CDK2. The effects of I3C are specific for this indole and not a consequence of the cell cycle arrest because treatment of MCF-7 breast cancer cells with either the I3C dimerization product DIM or the anti-estrogen tamoxifen induced a G1 cell cycle arrest with no changes in the associated cyclin E or subcellular localization of the CDK2 protein complex. Taken together, our results have uncovered a unique effect of I3C on cell cycle control in which the inhibition of CDK2 kinase activity is accompanied by selective alterations in cyclin E composition, size distribution, and subcellular localization of the CDK2 protein complex. 相似文献
17.
Reza Khayami Seyyed Reza Hashemi Mohammad Amin Kerachian 《Journal of cellular and molecular medicine》2020,24(16):8890-8902
The role of aldo‐keto reductase family 1 member B1 (AKR1B1) in cancer is not totally clear but growing evidence is suggesting to have a great impact on cancer progression. AKR1B1 could participate in a complicated network of signalling pathways, proteins and miRNAs such as mir‐21 mediating mechanisms like inflammatory responses, cell cycle, epithelial to mesenchymal transition, cell survival and apoptosis. AKR1B1 has been shown to be mostly overexpressed in cancer. This overexpression has been associated with inflammatory mediators including nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), cell cycle mediators such as cyclins and cyclin‐dependent kinases (CDKs), survival proteins and pathways like mammalian target of rapamycin (mTOR) and protein kinase B (PKB) or AKT, and other regulatory factors in response to reactive oxygen species (ROS) and prostaglandin synthesis. In addition, inhibition of AKR1B1 has been shown to mostly have anti‐cancer effects. Several studies have also suggested that AKR1B1 inhibition as an adjuvant therapy could render tumour cells more sensitive to anti‐cancer therapy or alleviate the adverse effects of therapy. AKR1B1 could also be considered as a potential cancer diagnostic biomarker since its promoter has shown high levels of methylation. Although pre‐clinical investigations on the role of AKR1B1 in cancer and the application of its inhibitors have shown promising results, the lack of clinical studies on AKR1B1 inhibitors has hampered the use of these drugs to treat cancer. Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers. 相似文献
18.
Priyankar Sanphui Sumit Kumar Pramanik Nandini Chatterjee Ponnusamy Moorthi Biswadip Banerji Subhas Chandra Biswas 《PloS one》2013,8(11)
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no cure till today. Aberrant activation of cell cycle regulatory proteins is implicated in neurodegenerative diseases including AD. We and others have shown that Cyclin dependent kinase 4 (Cdk4) is activated in AD brain and is required for neuron death. In this study, we tested the efficiency of commercially available Cdk4 specific inhibitors as well as a small library of synthetic molecule inhibitors targeting Cdk4 as neuroprotective agents in cellular models of neuron death. We found that several of these inhibitors significantly protected neuronal cells against death induced by nerve growth factor (NGF) deprivation and oligomeric beta amyloid (Aβ) that are implicated in AD. These neuroprotective agents inhibit specifically Cdk4 kinase activity, loss of mitochondrial integrity, induction of pro-apoptotic protein Bim and caspase3 activation in response to NGF deprivation. The efficacies of commercial and synthesized inhibitors are comparable. The synthesized molecules are either phenanthrene based or naphthalene based and they are synthesized by using Pschorr reaction and Buchwald coupling respectively as one of the key steps. A number of molecules of both kinds block neurodegeneration effectively. Therefore, we propose that Cdk4 inhibition would be a therapeutic choice for ameliorating neurodegeneration in AD and these synthetic Cdk4 inhibitors could lead to development of effective drugs for AD. 相似文献
19.
Xiaomin Han Jing Zhang Liang Guo Rihui Cao Yongzhen Li Ni Li Qin Ma Jialin Wu Yanchang Wang Shuyi Si 《PloS one》2012,7(10)
Polo-like kinases play an essential role in the ordered execution of mitotic events and 4 mammalian PLK family members have been identified. Accumulating evidence indicates that PLK1 is an attractive target for anticancer drugs. In this paper, a series of beta-carboline derivatives were synthesized and three compounds, DH281, DH285 and DH287, were identified as potent new PLK inhibitors. We employed various biochemical and cellular approaches to determine the effects of these compounds on the activity of PLK1 and other mitotic kinases and on cell cycle progression. We found that these three compounds could selectively inhibit the kinase activity of purified PLK1, PLK2 and PLK3 in vitro. They show strong antitumor activity against a number of cancer cell lines with relatively low micromolar IC50s, but are relatively less toxic to non-cancer cells (MRC5). Moreover, these compounds could induce obvious accumulation of HeLa cells in G2/M and S phases and trigger apoptosis. Although MRC5 cells show clear S-phase arrest after treatment with these compounds, the G2/M arrest and apoptosis are less insignificant, indicating the distinct sensitivity between normal and cancer cells. We also found that HeLa cells treated with these drugs exhibit monopolar spindles and increased Wee1 protein levels, the characteristics of cells treated with PLK1 inhibitors. Together, these results demonstrate that DH281, DH285 and DH287 beta-carboline compounds are new PLK inhibitors with potential for cancer treatment. 相似文献
20.
Feldman RI Wu JM Polokoff MA Kochanny MJ Dinter H Zhu D Biroc SL Alicke B Bryant J Yuan S Buckman BO Lentz D Ferrer M Whitlow M Adler M Finster S Chang Z Arnaiz DO 《The Journal of biological chemistry》2005,280(20):19867-19874
The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents. 相似文献