Effects of phosphoinositide 3-kinase inhibitor SHBM1009 on cancer cells proliferation

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Lingyan Wang ◽  
Li-Hao Huang ◽  
Qi Shen ◽  
Fangming Liu ◽  
Bijun Zhu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Cell Number ◽  
Pi3k Inhibitor ◽  
Therapeutic Effects ◽  
Recording Time ◽  
Cell Functions ◽  
Phosphoinositide 3 Kinase

BACKGROUND: Phosphoinositide 3-kinase (PI3K) plays an important role in cellular proliferation  and tumor progression. The objective of this study is to evaluate the potential mechanism and therapeutic effects of new PI3K inhibitor SHBM1009 on various cancer cells of digestive system on proliferation. METHODS: Six human hepatocellular carcinoma cell lines including 97H, 97L, A3, F11, MHCC-1, SMMC7721, one gastric cell line SGC-7901 and three primary testicular cancer TYST,TYST1,TYST2 cells were treated by 100ng/ml epidermal growth factor with or without 1uM NVP-BEZ-235 and SHBM1009  in Cell-IQ system in 24-well plates for 48h and up to 72h. The cell bio-behaviors, especially for cell proliferation of total cell number were measured by a real-time cell monitoring system, Cell-IQ continuous cell culturing platform. Images were captured at 30 min intervals. Cell-IQ system uses machine vision technology for monitoring and recording time-lapse data, and the cell functions and morphological parameters were quantified and analyzed. RESULTS: SHBM1009 could prevent EGF-induced cancer cells proliferation. Different patterns of inhibitory effects of SHBM1009 and NVP-BEZ-235, a dual PI3K/mechanistic target of rapamycin inhibitor, on EGF-induced cancer cells proliferation were observed. CONCLUSIONS: PI3K plays a critical role in the development of cancer progress, including proliferation, differentiation and anti-apoptosis. SHBM1009, a new PI3K inhibitor, could be new therapeutic alternatives for cancer treatment.

Effects of phosphoinositide 3-kinase inhibitor SHBM1009 on cancer cells proliferation

2018 ◽  
pp. 1-7
Author(s):  
Dujiao Wu ◽  
LiHao Huang ◽  
Qi Shen ◽  
Bijun Zhu
Keyword(s):  
Tumor Progression ◽  
Cancer Cells ◽  
Digestive System ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Pi3k Inhibitor ◽  
Therapeutic Effects ◽  
Potential Mechanism ◽  
Phosphoinositide 3 Kinase

Abstract: Phosphoinositide 3-kinase (PI3K) plays an important role in cellular proliferation and tumor progression. The objective of this study is to evaluate the potential mechanism and therapeutic effects of new PI3K inhibitor SHBM1009 on various cancer cells of digestive system on proliferation.  

Induction of Polyploidization in Leukemic Cell Lines and Primary Bone Marrow by Src Kinase Inhibitor SU6656.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2918-2918
Author(s):  
Brian J. Lannutti ◽  
Jennifer N. Minear ◽  
Noel Blake ◽  
Jonathan G. Drachman
Keyword(s):  
Bone Marrow ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Bone Marrow Cells ◽  
Therapeutic Potential ◽  
Present Report ◽  
Cell Number ◽  
Src Family Kinases ◽  
Murine Bone Marrow

Abstract Megakaryocytes (MKs) undergo successive rounds of endomitosis during differentiation, resulting in polyploidy (typically, 16-64N). Previous studies have demonstrated that this occurs through an interruption of normal cell cycle progression during anaphase. However, the molecular mechanism(s) controlling this unique process is undefined. Our studies of Src family kinases demonstrate that Lyn and Fyn kinases are activated by thrombopoietin (TPO) and have an inhibitory effect on cellular proliferation. In fact, adding PP1 to murine bone marrow cells in culture resulted in a higher percentage of polyploid cells. In the present report, we examined the effect of SU6656 on TPO-induced growth and differentiation. SU6656 is reported to be more specific than previous inhibitors for the Src family of tyrosine kinases. Remarkably, when SU6656 (2.5 mM) was added to a megakaryocytic cell line, UT-7/TPO, the cells underwent dramatic increase in cell size and polyploidization. By 24 h, 8N cells were present. After 48 h a 16N population was identified by FACS, and continued growth in SU6656 resulted in higher ploidy states (32N and 64N). This was accompanied by cessation of cellular proliferation (i.e. cell number remained constant), increase in CD41 and CD61 expression, and was notable for the absence of apoptosis. Similarly, polyploidization was observed when SU6656 was added to expanded human bone marrow progenitors with partial MK differentiation. The ability to induce differentiation was also seen using bone marrow from two patients with myelodysplastic syndrome and thrombocytopenia, suggesting that SU6656 might be useful as a differentiation-inducing agent for MKs. Although SU6656 is clearly a potent inhibitor of the Src family kinases, we have undertaken studies to determine if an additional target can be identified. We found no affect on Jak2, STAT3, and STAT5 tyrosine phosphorylation. However, the activity of Aurora kinase B was inhibited in vitro by as little as 50 nM SU6656. We propose that SU6656 may be an important tool for understanding the molecular basis of MK endomitosis and may also have therapeutic potential for individuals with MDS, thrombocytopenia, or other disorders resulting from incomplete megakaryocyte maturation.

scholarly journals Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway

2017 ◽  
Vol 44 (2) ◽  
pp. 581-593 ◽  
Author(s):  
Jijun Wang ◽  
Xiaolong Wang ◽  
Tong Chen ◽  
Liyu Jiang ◽  
Qifeng Yang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Transfection Efficiency ◽  
Critical Role ◽  
Protein A ◽  
Flow Cytometric Analysis ◽  
Therapeutic Effects ◽  
Protein Levels

Background/Aims: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression. Methods: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL. Results: Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p. Conclusion: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic

2007 ◽  
Vol 293 (1) ◽  
pp. C12-C21 ◽  
Author(s):  
Roberto Scatena ◽  
Patrizia Bottoni ◽  
Giorgia Botta ◽  
Giuseppe E. Martorana ◽  
Bruno Giardina
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Critical Role ◽  
Ion Homeostasis ◽  
Nucleoside Analogs ◽  
Therapeutic Effects ◽  
Mitochondrial Toxicity ◽  
Respiratory Chain Complexes

In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase-γ (pol-γ). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes. Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers. The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects.

scholarly journals Estrogen receptor β1 exerts antitumoral effects on SK-OV-3 ovarian cancer cells

2007 ◽  
Vol 193 (3) ◽  
pp. 421-433 ◽  
Author(s):  
Oliver Treeck ◽  
Georg Pfeiler ◽  
Diana Mitter ◽  
Claus Lattrich ◽  
Gerhard Piendl ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Splice Variants ◽  
Ovarian Cancer Cell Line ◽  
Regulation Of Gene Expression ◽  
Ovarian Cancer Cells ◽  
Mrna Levels

Estrogen receptor (ER) β1 and its splice variants are expressed both in ovary and ovarian cancer. We studied the role of ERβ1 and two of its splice variants in regulation of gene expression, cellular proliferation, apoptosis, and migration of an ovarian cancer cell line. In this study, we transfected SK-OV-3 ovarian cancer cells with vectors coding for ERβ1 or its splice variants ERβ-δ125 and ERβ-δ1256, and tested their response to estrogen and tamoxifen in comparison with the untransfected cells. Heterologous expression of ERβ1, but not of the exon-deleted ERβ variants resulted in notably slower cell growth of SK-OV-3 ovarian cancer cells, an effect accompanied by more than tenfold increase of cyclin-dependent kinase inhibitor p21(WAF1) transcript levels and a significant reduction of cyclin A2 mRNA levels. SK-OV-3 cells stably overexpressing ERβ1 ligand independently also exhibited an increased apoptosis rate and a significantly decreased motility, an effect accompanied by upregulation of fibulin 1c. Our data demonstrate that ERβ1, but not the exon-deleted isoforms tested exerts multiple antitumoral effects on SK-OV-3 ovarian cancer cells even in the absence of estradiol or functional ERα.

scholarly journals Targeting a moonlighting function of aldolase induces apoptosis in cancer cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Agnieszka Gizak ◽  
Janusz Wiśniewski ◽  
Paul Heron ◽  
Piotr Mamczur ◽  
Jurgen Sygusch ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cellular Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Atp Synthesis ◽  
Pharmacological Action ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Catalytic Function

Abstract Muscle fructose-1,6-bisphosphate aldolase (ALDOA) is among the most abundant glycolytic enzymes in all cancer cells. Here, we show that the enzyme plays a previously unknown and critical role in a cancer cell survival. Simultaneous inhibition of ALDOA activity and interaction with F-actin cytoskeleton using ALDOA slow-binding inhibitor UM0112176 leads to a rapid cofilin-dependent loss of F-actin stress fibers which is associated with elevated ROS production, inhibition of ATP synthesis, increase in calcium levels, caspase activation and arrested cellular proliferation. These effects can be reproduced by silencing of ALDOA. The mechanism of pharmacological action is, however, independent of the catalytic function of the enzyme, specific to cancer cells, and is most deleterious to cells undergoing the epithelial–mesenchymal transition, a process facilitating cancer cell invasion. Our results demonstrate that the overabundance of ALDOA in cancer cells is associated with its moonlighting rather than catalytic functions. This may have significant implications for development of novel broad-based anti-cancer therapies.

scholarly journals p21cip1/waf1 Coordinates Autophagy, Proliferation and Apoptosis in Response to Metabolic Stress

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1112 ◽  
Author(s):  
Kanjoormana Manu ◽  
Pham Cao ◽  
Tin Chai ◽  
Patrick Casey ◽  
Mei Wang
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Biological Significance ◽  
Metabolic Stress ◽  
Exciting Field ◽  
Cell Functions ◽  
Metabolic Properties ◽  
Chemotherapeutic Treatment

Cancer cells possess metabolic properties that are different from benign cells. These unique characteristics have become attractive targets that are being actively investigated for cancer therapy. p21cip1/waf1, also known as Cyclin-Dependent Kinase inhibitor 1A, is encoded by the CDKN1A gene. It is a major p53 target gene involved in cell cycle progression that has been extensively evaluated. To date, p21 has been reported to regulate various cell functions, both dependent and independent of p53. Besides regulating the cell cycle, p21 also modulates apoptosis, induces senescence, and maintains cellular quiescence in response to various stimuli. p21 transcription is induced in response to stresses, including those from oxidative and chemotherapeutic treatment. A recent study has shown that in response to metabolic stresses such as nutrient and energy depletion, p21 expression is induced to regulate various cell functions. Despite the biological significance, the mechanism of p21 regulation in cancer adaptation to metabolic stress is underexplored and thus represents an exciting field. This review focuses on the recent development of p21 regulation in response to metabolic stress and its impact in inducing cell cycle arrest and death in cancer cells.

scholarly journals Survivin in breast cancer–derived exosomes activates fibroblasts by up-regulating SOD1, whose feedback promotes cancer proliferation and metastasis

2020 ◽  
Vol 295 (40) ◽  
pp. 13737-13752 ◽  
Author(s):  
Kangdi Li ◽  
Ting Liu ◽  
Jie Chen ◽  
Huying Ni ◽  
Wenhua Li
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Breast Cancer Progression ◽  
Mesenchymal Transition ◽  
Cell Functions

Cancer-associated fibroblasts (CAFs) play a critical role in the coevolution of breast tumor cells and their microenvironment by modifying cellular compartments and regulating cancer cell functions via stromal-epithelial dialogue. However, the relationship and interaction between stromal and epithelial cells is still poorly understood. Herein, we revealed that breast cancer cells have a stronger ability to activate fibroblasts and transform them into myofibroblasts (CAF-like) than normal breast epithelial cells, and this stronger ability occurs through paracrine signaling. In turn, myofibroblasts promote the proliferation, epithelial-to-mesenchymal transition (EMT), and stemness of breast cancer cells. Detailed regulatory mechanisms showed that, compared with normal cells, Survivin is overexpressed in breast cancer cells and secreted extracellularly in the form of exosomes, which are then internalized by fibroblasts. Breast cancer cell–derived survivin up-regulates SOD1 expression in fibroblasts and then converts them into myofibroblasts, conversely inducing breast cancer progression in vitro and in vivo. Thus, our results indicate that survivin acts as an activator of the tumor microenvironment and that SOD1 up-regulation in fibroblasts can promote breast cancer progression. These results suggest that targeting survivin and SOD1 may be a potential therapeutic strategy for breast cancer.

scholarly journals Ion channels and apoptosis in cancer

2014 ◽  
Vol 369 (1638) ◽  
pp. 20130104 ◽  
Author(s):  
Carl D. Bortner ◽  
John A. Cidlowski
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Ion Channels ◽  
Cell Growth ◽  
Cancer Cells ◽  
Critical Role ◽  
Cell Number ◽  
Tumour Formation ◽  
Constant Cell ◽  
Critical Components

Humans maintain a constant cell number throughout their lifespan. This equilibrium of cell number is accomplished when cell proliferation and cell death are kept balanced, achieving a steady-state cell number. Abnormalities in cell growth or cell death can lead to an overabundance of cells known as neoplasm or tumours. While the perception of cancer is often that of an uncontrollable rate of cell growth or increased proliferation, a decrease in cell death can also lead to tumour formation. Most cells when detached from their normal tissue die. However, cancer cells evade cell death, tipping the balance to an overabundance of cell number. Therefore, overcoming this resistance to cell death is a decisive factor in the treatment of cancer. Ion channels play a critical role in cancer in regards to cell proliferation, malignant angiogenesis, migration and metastasis. Additionally, ion channels are also known to be critical components of apoptosis. In this review, we discuss the modes of cell death focusing on the ability of cancer cells to evade apoptosis. Specifically, we focus on the role ion channels play in controlling and regulating life/death decisions and how they can be used to overcome resistance to apoptosis in the treatment of cancer.

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