scholarly journals A screen of kinase inhibitors reveals a potential role of Chk1 in regulating Hydra head regeneration and maintenance

2021 ◽  
Author(s):  
Yunjin Lee ◽  
Varun Muddaluru ◽  
Shiraz Anwar ◽  
Joanna Yvonne Wilson ◽  
Ana Regina Campos
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Relative Proportion ◽  
Body Parts ◽  
G2 Checkpoint ◽  
Evolutionarily Conserved ◽  
Chk1 Inhibitor ◽  
Head Regeneration

The cnidarian Hydra possesses remarkable regenerative capabilities which allows it to regrow lost or damaged body parts in a matter of days. Given that many key regulators of regeneration and development are evolutionarily conserved, Hydra is a valuable model system for studying the fundamental molecular mechanisms underlying these processes. In the past, kinase inhibitors have been useful tools for determining the role of conserved signaling pathways in Hydra regeneration and patterning. Here, we present a systematic screen of a commercially available panel of kinase inhibitors for their effects on Hydra regeneration. Isolated Hydra gastric segments were exposed to 5 µM of each kinase inhibitor and regeneration of the head and foot regions were scored over a period of 96 hours. Of the 80 kinase inhibitors tested, 28 compounds resulted in abnormal regeneration. We directed our focus to the checkpoint kinase 1 (Chk1) inhibitor, SB 218078, considering the role of Chk1 in G2 checkpoint regulation and the importance of G2-paused cells in Hydra regeneration. We found that Hydra exposed to SB 218078 were unable to regenerate the head and maintain head-specific structures. Furthermore, SB 218078-treated Hydra displayed a reduction in the relative proportion of epithelial cells, however no differences were seen for interstitial stem cells or their derivatives. Lastly, exposure to SB 218078 appeared to have no impact on the level of mitosis or apoptosis. Overall, our study demonstrates the feasibility of kinase inhibitor screens for studying Hydra regeneration processes and highlights the possible role for Hydra Chk1 in head regeneration and maintenance.

Abstract 170: Mechanism of Cardiotoxicity of Tyrosine Kinase Inhibitors

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Manar F Elmadani ◽  
Johanna Ulvila ◽  
Suleiman Khan ◽  
Tarja Alakoski ◽  
Johanna Magga ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Erk Pathway ◽  
Wild Type ◽  
Erk Phosphorylation ◽  
Dasatinib Treatment

Aim: It is becoming evident that many of the signaling elements driving cancer cell division, for which kinase inhibitors (KIs) are targeted, are the same as those necessary for cardiomyocyte viability. Adverse cardiac events have been reported for a number of KIs. Aim of this study was to identify KIs that induce toxicity to cardiomyocytes and to elucidate the central molecular mechanisms mediating the toxicity. Methods: 288 anti-cancer agents (123 are KIs) were screened for their ability to induce cardiotoxicity in cultured primary cardiomyocytes. Cell viability assay was done by measuring the ATP levels in cardiomyocytes after exposure of cells to a 3-log concentration range of each compound for 24 hours. Toxicity data was combined with kinase profiling data to identify protein kinases mediating the toxicity of KIs. In parallel, the molecular mechanism mediating the cardiomyocyte toxicity of dasatinib, a second generation Bcr-Abl and Src family tyrosine kinase inhibitor, was investigated. The role of Src kinase in regulation of cardiomyocyte viability was analyzed by siRNA-mediated Src knockdown. Overexpression of wild type Src and dasatinib- resistant Src in cardiomyocytes was performed to investigate the role of Src in regulating the cardiomyocyte toxicity of dasatinib. Western blotting was used to investigate for downstream signaling targets of Src. Results: Of the KIs, 70 compounds decreased the cardiomyocyte viability by 10-80 %. The kinase profiling data showed that IGF1R, MEK/ERK pathway, PI3K and Src kinases are the key kinases regulating cardiomyocyte viability. Dasatinib treatment dose-dependently increased cardiomyocyte death. Depletion of Src by siRNA also reduced cardiomyocyte viability. Dasatinib treatment attenuated FGF induced ERK phosphorylation. Overexpression of dasatinib-resistant mutant of Src, but not wild type Src, protected the cardiomyocyte from dasatinib toxicity and rescued the FGF-induced ERK phosphorylation. Conclusions: Cardiomyocyte toxicity of KIs can be attributed to inhibition of IGF1R, MEK/ERK pathway, PI3Ks and Src family kinases. Cardiomyocyte toxicity of dasatinib is mediated by Src kinase inhibition which in turn attenuates MEK/ERK pathway signalling.

scholarly journals ROLE OF SERIN/ THREONINE KINASE INHIBITOR IN THERAPY NON-ALCOHOLIC STEATOHEPATITIS AND ALCOHOLIC HEPATITIS

2019 ◽  
Vol 6 (3) ◽  
pp. 101-109
Author(s):  
Novriantika Lestari
Keyword(s):  
Signal Transduction ◽  
Liver Fibrosis ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Binding Activity ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Receptor Binding Activity ◽  
Marked Accumulation

Liver fibrosis is a reversible response to a wound healing with marked accumulation of extracellular matrix which caused by injury to the liver. Liver fibrosis can be caused by various factors including alcohol and non-alcohol steatohepatitis. The process of fibrosis serves to localize the inflammation during chronic exposure. The hepatic stem cell (HSC) has a key role in the pathogenesis of liver fibrosis. The HSC activation is characterized by increased profibrogenic mediators including members of the TGF-? superfamily. In order to enable signal transduction, the mediator needs to bind to its receptors. The serine/ threonine kinase receptor is a receptor that binds to the TGF-? superfamily ligand, including TGF-?, BMP, activin and other mediators. The ligand receptor-binding activity will stimulate signal transduction that will translocate into the nucleus and phosphorylate various transcription factors that play a role in cell proliferation, differentiation, or apoptosis. There is currently no standard therapy for liver fibrosis. Based on the central role of the serine/ threonine kinase receptor in the pathogenesis of liver fibrosis, it is thought that the use of serine/ threonine kinase inhibitors is a promising therapy.

The patient with renal cell cancer

2015 ◽  
Author(s):  
Tim Eisen
Keyword(s):  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cancer ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cell Cancer

Renal cancer is the commonest malignancy of the kidney and worldwide, accounts for between 2% and 3% of the total cancer burden. The mainstay of curative treatment remains surgery. There have been significant advances in surgical technique, the most important ones being nephron-sparing surgery and laparoscopic nephrectomy. The medical treatment of advanced renal cell cancer has only improved markedly in the last decade with the development of antiangiogenic tyrosine-kinase inhibitors, inhibitors of mammalian target of rapamycin, and a diminished role for immunotherapy.Tyrosine-kinase inhibitor therapy results in reduction of tumour volume in around three-quarters of patients and doubles progression-free survival, but treatment is not curative. The management of side effects in patients on maintenance tyrosine-kinase inhibitors has improved in the last 3 years, although still presents difficulties which have to be actively considered.The molecular biology of renal cell carcinoma is better understood than for the majority of solid tumours. The commonest form of renal cancer, clear-cell carcinoma of the kidney, is strongly associated with mutations in the von Hippel–Lindau gene and more recently with chromatin-remodelling genes such as PBRM1. These genetic abnormalities lead to a loss of control of angiogenesis and uncontrolled proliferation of tumour cells. There is a very wide spectrum of tumour behaviour from the extremely indolent to the terribly aggressive. It is not currently known what accounts for this disparity in tumour behaviour.A number of outstanding questions are being addressed in scientific and clinical studies such as a clearer understanding of prognostic and predictive molecular biomarkers, the role of adjuvant therapy, the role of surgery in the presence of metastatic disease, how best to use our existing agents, and investigation of novel targets and therapeutic agents, especially novel immunotherapies.

scholarly journals The role of FLOWERING LOCUS C in vernalization of Brassica: the importance of vernalization research in the face of climate change

2018 ◽  
Vol 69 (1) ◽  
pp. 30 ◽  
Author(s):  
Daniel J. Shea ◽  
Etsuko Itabashi ◽  
Satoko Takada ◽  
Eigo Fukai ◽  
Tomohiro Kakizaki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Model Organism ◽  
Climatic Changes ◽  
Environmental Cues ◽  
Plant Responses ◽  
Agricultural Crops ◽  
Regulatory Pathways ◽  
Evolutionarily Conserved ◽  
The Face

As climatic changes occur over the coming decades, our scientific understanding of plant responses to environmental cues will become an increasingly important consideration in the breeding of agricultural crops. This review provides a summary of the literature regarding vernalization research in Brassicaceae, covering both the historical origins of vernalization research and current understanding of the molecular mechanisms behind the regulatory pathways involved in vernalization and subsequent inflorescence. We discuss the evolutionarily conserved biology between the model organism Arabidopsis thaliana and the Brassica genus of crop cultivars and contrast the differences between the genera to illustrate the importance of Brassica-specific research into vernalization.

Bafetinib inhibits ishikawa cells growth through modulating p16 expression

2017 ◽  
Vol 6 (3) ◽  
pp. 42
Author(s):  
Mohammad Althubiti
Keyword(s):  
Endometrial Cancer ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Ishikawa Cell ◽  
Proliferative Effect ◽  
Cycle Arrest ◽  
Ishikawa Cells ◽  
And Control ◽  
P16 Expression

Bafetinib is a tyrosine kinase inhibitor of Lyn- BCR/ABL that has been used experimentally for leukemia therapy. From our previous experimental work with bafetinib, it showed an anti-proliferative effect on Ishikawa cell line at concentration of 200nM. This observation was supported by colonogenic assay, the number of colonies formed by Ishikawa cells was 6 folds in the control comparing to bafetinib treated cells. Cells counting also support this finding, Ishikawa treated cells were unable to continue growing after 2 days of the drug addition comparing to the control cells that continued dividing. This underscores the role of bafetinib as anti-neoplastic agent on Ishikawa cells. To understand its mechanism of action, cyclin-dependent kinase inhibitors p16INK4a and p21 WAF1 that have major role in cell cycle arrest were measured. No difference was noticed in p21 levels between the treated and control cells; however, increasing in p16 expression was observed in treated Ishikawa cells. This underlines the role of bafetinib in inhibiting Ishikawa cells through modulating p16 expression. This suggests that bafetinib could be used as a therapy in case of endometrial cancer. But, further work should be conducted to examine the effect of bafetinib on other endometrial cancer cells and on mice before testing its effect on endometrial cancer patients.

V600E mutations in metastatic melanoma: Case report.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20002-e20002 ◽  
Author(s):  
Momcilo Inic ◽  
Zorka Momcilo Inic ◽  
Milan Zegarac ◽  
Gordana Pupic ◽  
Ivana Inic
Keyword(s):  
Metastatic Melanoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Tumor Regression ◽  
Relative Reduction ◽  
Ankle Joints ◽  
Deposit Type ◽  
Progression Risk ◽  
Braf V600 Mutation

e20002 Background: Vemurafenib, a selective BRAF kinase inhibitor, is a new medicine against carcinoma.This work will discuss new approaches to the treatment of patients with metastatic melanoma, who have been proved to have BRAF V600 mutation. Methods: The 62-year-old patient was initially diagnosed in 2002 when the excision of melanoma of the left calf was performed. HP was Melanoma invasivum nodular, Breslow III, Clark IV, p T3, without angioinvasion. The stadium of illness was M1a (AJCC). Afterwards, she was operated four times. Chemyotherapy was performed with DTIC and in the further treatment secundary HT VLB-BLM-CDDP. In June 2012 the examination of the control ultrasound of the abdomen and pelvis registered the progression of illness. The liver indicated multiple changes of seundary deposit type, the largest of which was 24mm parailiac left lgl 53mm, inguinal left 23mm. It was confirmed that the patient had the mutation on the BRAF gene and she was included in the clinical study in the illness stadium M1c (AJCC). Subsequently the therapy with vemurafenib 960 mg twice a day was introduced, after which side effects were registered: rash gr. 2, arthralgia gr. 1 (pain in the hand joints) and the swelling of ankle joints gr. 1. The patient continued the vemurafenib therapy. At the latest examination in October 2012, the control CT screening registered the regression of secundary deposit by 40%. Results: Identifying the significance of BRAF has led to the development of numerous new medicines against carcinoma. One of them is vemurafenib (PLKS4032), a medicine inhibiting particularly BRAF V600 mutation. Stage I of studying this medicine showed a complete or partial tumor regression in 81% patients with V600 BRAF mutation, while stage showed a relative reduction of death risk in 63% patients, as well as a relative reduction of tumor progression risk in 74% patients in comparison to dakarbazin. Still, patients who take vemurafenib develop resistance to this medicine within 7 months on average. Conclusions: The development of vemurafenib and the role of BRAF targeted therapy in the treatment of metastatic melanoma ensure a new basis for the clinical research. Further clinical studies will research complex molecular mechanisms underlying resistance and toxicity to vemurafenib.

scholarly journals Recent progress in research on molecular mechanisms of autophagy in the heart

2015 ◽  
Vol 308 (4) ◽  
pp. H259-H268 ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yun Chen ◽  
Mitsuaki Isobe ◽  
Åsa B. Gustafsson ◽  
Richard N. Kitsis ◽  
...  
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Degradation Process ◽  
Structure And Function ◽  
Cellular Functions ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Cellular Dysfunction

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

scholarly journals Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice

2020 ◽  
Author(s):  
Francois Singh ◽  
Alan R. Prescott ◽  
Graeme Ball ◽  
Alastair D. Reith ◽  
Ian G. Ganley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Neurodegenerative Disorder ◽  
Reporter Mice ◽  
Lrrk2 G2019s ◽  
Lrrk2 Kinase

AbstractParkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy. Here we investigated the role of LRRK2, a protein kinase frequently mutated in PD, on this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson’s disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.

Tyrosine Kinase Inhibitor-Induced Hypertension: Role of Hypertension as a Biomarker in Cancer Treatment

2019 ◽  
Vol 17 (6) ◽  
pp. 618-634 ◽  
Author(s):  
Cecilie Budolfsen ◽  
Julie Faber ◽  
Daniela Grimm ◽  
Marcus Krüger ◽  
Johann Bauer ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Tyrosine Kinase ◽  
Cancer Treatment ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Prognostic Models ◽  
Capillary Rarefaction ◽  
Potential Biomarker ◽  
Tki Treatment

:Cancer treatment is an area of continuous improvement. Therapy is becoming more targeted and the use of anti-angiogenic agents in multiple cancers, specifically tyrosine kinase inhibitors (TKIs), has demonstrated prolonged survival outcomes compared with previous drugs. Therefore, they have become a well-established part of the treatment.:Despite good results, there is a broad range of moderate to severe adverse effects associated with treatment. Hypertension (HTN) is one of the most frequent adverse effects and has been associated with favourable outcomes (in terms of cancer treatment) of TKI treatment.:High blood pressure is considered a class effect of TKI treatment, although the mechanisms have not been fully described. Three current hypotheses of TKI-associated HTN are highlighted in this narrative review. These include nitric oxide decrease, a change in endothelin-1 levels and capillary rarefaction.:Several studies have investigated HTN as a potential biomarker of TKI efficacy. HTN is easy to measure and adding this factor to prognostic models has been shown to improve specificity. HTN may become a potential biomarker in clinical practice involving treating advanced cancers. However, data are currently limited by the number of studies and knowledge of the mechanism of action.

HOXA10 Expression Induces by Abl Kinase Inhibitors Enhanced Apoptosis through PI3K Pathway in CML Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4529-4529
Author(s):  
Isao Hirano ◽  
Yuya Sugimoto ◽  
Keiji Okinaka ◽  
Takaaki Ono ◽  
Kaori Shinjo ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Pi3k Pathway ◽  
Hematopoietic Progenitor ◽  
Leukemic Transformation ◽  
Hematopoietic Stem ◽  
Abl Kinase ◽  
Abl Kinase Inhibitors

Abstract [Background] Homeobox (Hox) genes are grouped together in 4 clusters, A to D. Recent studies has shown that the Hox proteins are important in the control of differentiation and proliferation in hematopoietic cells. We found that the Abl kinase inhibitors increased the expression of HoxA10 gene in CML cells. In this study, we analyzed the role of HoxA10 in CML cell lines and the hematopoietic progenitor cells derived from CML patients by inhibiting the expression of HoxA10. Moreover, we investigated whether the regulation of HoxA10 eradicate Ph+ hematopoietic stem/progenitor cells, which are the targets for leukemic transformation in CML. [Methods] We used AMN107 and BMS354825 for the Abl kinase inhibitors, LY294002 for a PI3K inhibitor, PP2 for a Src kinase inhibitor, and SB203580 for a p38 MAP kinase inhibitor. For analysis of HoxA10 mRNA and protein, RT-PCR and western blot were performed in K562, Meg-01 and U937 cells, which untreated or treated with AMN107, BMS354825, LY294002, PP2, or SB203580 respectively. We then attempted to localize the intracellular locations of HoxA10 in K562 and Meg01, which untreated or treated with AMN107, BMS354825, or LY294002 by using conforcal fluorescence microscopy. For analysis of proliferation in K562, Meg-01 and U937 transfected with siRNA HoxA10, MTT assays were performed in untransfected or transfected K562, Meg-01 and U937 treated with or without AMN107, BMS354825, or LY294002. Finally, we counted the colony numbers of CFU-GEMM, CFU-GM, and BFU-E in K562 and Meg-01 treated with the Abl kinase inhibitors or LY294002. Results Both K562 and Meg01 cells expressed HoxA10 mRNA and protein at lower level compared to U937 cells. Interestingly, treatment with AMN107, BMS354825, or LY294002 increased the expression of HoxA10 mRNA and protein in both K562 and Meg01 cells. The fluorescence of HoxA10 was more strongly observed in the area corresponding to the cell’s cytoplasm than nucleus, and the treatment with AMN107, BMS354825, or LY294002 increased the fluorescence in nucleus of K562 and Meg01 cells in a time-dependent manner. In K562 and Meg01 cells transfected with the siRNA HoxA10, treatment with AMN107 or BMS354825 slightly inhibited the proliferation compared to K562 and Meg01 transfected with control siRNA. Finally, we showed that the inhibition of HoxA10 expression by siRNA increased the numbers of CFU-GEMM, BFU-E, and CFU-GM when the cells were treated with the combination of BMS354825 and LY294002 compared to control cells. [Conclusions] In this study, we showed that the Abl kinase inhibitors induced the expression of HoxA10, and HoxA10 was regulated by PI3K pathway in CML cells. This finding indicates a new insight in the regulation of cell proliferation via the PI3K signal pathway in CML cells. Moreover, we found the role of HoxA10 in CML cell lines and the hematopoietic progenitor cells derived from CML patients by inhibiting the expression of HoxA10. We showed that the regulation of HoxA10 eradicated Bcr-Abl+ hematopoietic stem/progenitor cells, which are the targets for leukemic transformation in CML.

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