Effects of gefitinib and vandetanib on human equilibrative nucleoside transporter 1 and on gemcitabine cytotoxicity.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2546-2546
Author(s):  
Vijaya L. Damaraju ◽  
Tara Scriver ◽  
Delores Mowles ◽  
Carol E Cass ◽  
Michael B. Sawyer
Keyword(s):  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
A549 Cells ◽  
Nucleoside Transporter ◽  
Chemotherapy Drugs ◽  
Protein Levels ◽  
Uridine Uptake ◽  
Pharmacokinetic Properties ◽  
Added Benefit

2546 Background: Combination chemotherapy with tyrosine kinase inhibitors (TKIs) and gemcitabine has been attempted with little added benefit to patients. We hypothesized that TKIs that were designed to bind to ATP pockets of growth factor tyrosine kinases also bind to proteins that recognize nucleosides, thereby potentially interfering with gemcitabine pharmacology. Methods: Interaction of TKIs with human nucleoside transporters (NTs) was studied using recombinant NTs produced in yeast. Effects of TKIs on uridine transport, gemcitabine transport and accumulation, regulation of NT activity and cytotoxicity with and without gemcitabine were evaluated in human A549 lung cancer cells. Results: In yeast, vandetanib inhibited two equilibrative NTs (hENT1, hENT2) and three concentrative NTs (hCNT1, hCNT2, hCNT3) with the greatest inhibition seen with hENT1 whereas gefitinib strongly inhibited hENT1 and hCNT1 only. In A549 cells, which possess major hENT1 and minor hENT2 activities, [3H]uridine uptake was inhibited by vandetanib and gefitinib with IC50 values of 16 ± 4 and 5 ± 0.3µM, respectively. Both TKIs also inhibited [3H]gemcitabine transport and accumulation in A549 cells. hENT1 protein levels were decreased during exposures to vandetanib or gefitinib for 24 hours, and cytotoxicity was greatest when gemcitabine was given prior to vandetanib or gefitinib. Conclusions: Vandetanib and gefitinib inhibited human NTs, especially hENT1, resulting in reduced intracellular gemcitabine accumulation. Gefitinib or vandetanib levels achieved in plasma and tumor tissues are sufficient to inhibit hENT1 activity. Because TKIs can block uptake of nucleoside chemotherapy drugs in cultured cancer cells, attention must be paid to TKIs and nucleoside pharmacokinetic properties when scheduling TKIs and nucleoside chemotherapy.

scholarly journals The Effect of Compound Sophora on Fluorouracil and Oxaliplatin Resistance in Colorectal Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
WeiHua Yin ◽  
GuPing Zhong ◽  
HuiZhen Fan ◽  
HongMei Xia
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Sw480 Cell ◽  
Gastric Cancer Cells ◽  
Glycoprotein P ◽  
Chemotherapy Drugs ◽  
Protein Levels ◽  
Enhanced Expression

Fluorouracil (5-FU) and oxaliplatin (L-OHP) are the most commonly used chemotherapy drugs for colorectal cancer, though resistance is common. Compound Sophora injection is a traditional Chinese medicine that can protect the liver against oxidation, improve immunity, and enhance sensitivity to chemotherapy; it may have an effect of reversing resistance in 5-FU- and L-OHP-resistant gastric cancer cells (5-FU/SW480 and L-OHP/SW480, respectively). A concentration gradient experiment was performed to identify a nontoxic dose of compound Sophora injection. 5-FU/SW480 and L-OHP/SW480 cells were treated with the nontoxic dose of compound radix Sophorae injection for 48 h, and changes in drug resistance to 5-FU and L-OHP were detected. Alterations in apoptosis and the cell cycle were assessed, as were the mRNA and protein levels of permeability glycoprotein (P-gp), annexin A1 (ANXA1), and ATP-binding cassette superfamily G member 2 (ABCG2). Flow cytometry showed a reduction in the number of cells in the G1 phase and an increase of cells in the S phase (P<0.05). mRNA and protein expression of P-gp and ABCG2 was significantly higher in 5-FU/SW480 and L-OHP/SW480 cell lines, and ANXA1 expression decreased significantly (P<0.05). Compound Sophora injection can reverse the drug resistance of 5-FU/SW480 and L-OHP/SW480 cell lines to 5-FU and L-OHP, respectively, possibly through a mechanism involving reduced expression of P-gp and ABCG2 but enhanced expression of ANXA1, which is the basis for the identification of clinical drug resistance in colorectal cancer.

scholarly journals SORLA-driven endosomal trafficking regulates the oncogenic fitness of HER2

2018 ◽  
Author(s):  
Mika Pietilä ◽  
Pranshu Sahgal ◽  
Emilia Peuhu ◽  
Niklas Jäntti ◽  
Ilkka Paatero ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Endosomal Trafficking ◽  
Oncogenic Signaling ◽  
Membrane Expression ◽  
Cationic Amphiphilic Drugs ◽  
Amphiphilic Drugs

AbstractHuman epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. Endosomal trafficking of many other receptor tyrosine kinases regulates their oncogenic signaling, but the prevailing view is that HER2 is retained on the cell surface. Here we reveal that in cancer cells Sortilin related receptor 1 (SORLA; SORL1) forms a complex with HER2 and regulates its subcellular distribution by promoting recycling of endosomal HER2 back to plasma membrane. Expression of SORLA in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA targets HER2 to late endosomal/lysosomal compartments, impairs HER2-driven signaling and in vivo tumor growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

scholarly journals Polyisoprenylated Cysteinyl Amide Inhibitors Deplete K-Ras and Induce Caspase-dependent Apoptosis in Lung Cancer Cells

2019 ◽  
Vol 19 (10) ◽  
pp. 838-851 ◽  
Author(s):  
Augustine T. Nkembo ◽  
Felix Amissah ◽  
Elizabeth Ntantie ◽  
Rosemary A. Poku ◽  
Olufisayo O. Salako ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Fold Increase ◽  
Lung Cancer Cells ◽  
Ras Signaling ◽  
Extrinsic Pathway ◽  
Lung Cancers ◽  
Protein Levels

Background: Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation of Ras signaling present some of the most difficult-to-manage cases, since directly targeting the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. Objective: In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. Methods: The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid and colony formation were determined. Results: Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA- 040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549, NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563) NSCLC cells. The PCAIs at 1.0 -10 μM induced the degeneration of 3D spheroid cultures, inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most potent of the PCAIs, NSL-BA-055, at 5 μM induced a seven-fold increase in the activity of caspase- 3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation of MAP kinase (ERK 1/2). Conclusion: Taken together, PCAIs may be potentially useful as targeted therapies that suppress NSCLC progression through disruption of Ras-mediated growth signaling.

scholarly journals Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
D. Samuel Metibemu ◽  
O. Adeboye Akinloye ◽  
A. Jamiu Akamo ◽  
D. Ajiboye Ojo ◽  
O. Tolulope Okeowo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Conformational Changes ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
Acquired Resistance ◽  
Cellular Growth ◽  
Tyrosine Kinase Domain

Abstract Background Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount. MainText Tyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor’s extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation. Conclusions Understanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.

T4 Reduces Cisplatin Resistance by Inhibiting AEG-1 Gene Expression in Lung Cancer Cells

2020 ◽  
Author(s):  
Tianjiao Song ◽  
Xiaohong Lin ◽  
Pingting Huang ◽  
Yuqing Chen ◽  
Limin Chen
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
A549 Cells ◽  
Lethal Effect ◽  
Lung Cancer Cells ◽  
Chemotherapeutic Drugs ◽  
Lung Cancer Patients ◽  
Chemotherapy Drugs ◽  
Mdr 1

Abstract BackgroundLung cancer is one of the deadliest diseases in the world. Most lung cancer patients are resistant to chemotherapy drugs. In our study, we investigated whether T4 can reduce the resistance of lung cancer cells to chemotherapeutic drugs through the action of AEG-1.Materials and Methods1.A549 and A549/DDP cells were respectively transfected with overexpressing AEG-1 and knockdown AEG-1 plasmid. A549 and A549/DDP cells were added 0、25、50、100、200nM T4 respectively. 200nM T4 was selected for following experiments. A549/DDP cells were divided into A549/DDP empty group, T4 group, T4+AEG-1 overexpressing group. CCK8 assay was used to detect the proliferation of cells in each group. RT-qPCR and Western blotting were used to detect the expression of AEG-1 and MDR-1.ResultsAs expected, the expression of AEG-1 in A549 and A549/DDP cells is positively correlated with cisplatin resistance. When AEG-1 protein was overexpressed in A549 cells, the lethal effect of cisplatin on A549 cells was attenuated (all P<0.05). After AEG-1 protein was knocked down in A549/DDP cells, cisplatin was applied to the A549/DDP cells. The lethal effect was significantly increased compared to that in the control cells (all P<0.05). The expression of AEG-1 protein gradually decreased with increasing concentration of T4 in A549 and A549/DDP cells; The resistance to cisplatin was reduced after the addition of T4 to A549/DDP cells (P<0.05), and this effect was enhanced after transfection with the AEG-1 plasmid. ConclusionIn summary, T4 is important for increasing the sensitively of lung cancer cells to cisplatin. AEG-1 may be a key protein involved in this effect and may have an important impact on the survival rate of chemotherapy in patients with lung cancer in the future.

scholarly journals Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor

2009 ◽  
Vol 422 (3) ◽  
pp. 433-442 ◽  
Author(s):  
Nicole K. Noren ◽  
Nai-Ying Yang ◽  
Morgan Silldorff ◽  
Ravi Mutyala ◽  
Elena B. Pasquale
Keyword(s):  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Single Amino Acid ◽  
Cell Contact ◽  
Eph Receptors ◽  
Independent Manner ◽  
Protein Levels ◽  
Substrate Adhesion ◽  
Cell Substrate ◽  
Cell Substrate Adhesion

Receptor tyrosine kinases of the Eph family become tyrosine phosphorylated and initiate signalling events upon binding of their ligands, the ephrins. Eph receptors such as EphA2 and EphB4 are highly expressed but poorly tyrosine phosphorylated in many types of cancer cells, suggesting a limited interaction with ephrin ligands. Nevertheless, decreasing the expression of these receptors affects the malignant properties of cancer cells, suggesting that Eph receptors may influence cancer cells independently of ephrin stimulation. Ligand-independent activities of Eph receptors in cancer, however, have not been demonstrated. By using siRNA (small interfering RNA) to downregulate EphB4 in MCF7 and MDA-MB-435 cancer cells, we found that EphB4 inhibits integrin-mediated cell substrate adhesion, spreading and migration, and reduces β1-integrin protein levels. Low expression of the EphB4 preferred ligand, ephrin-B2, and minimal contact between cells in these assays suggest that cell contact-dependent stimulation of EphB4 by the transmembrane ephrin-B2 ligand does not play a role in these effects. Indeed, inhibitors of ephrin-B2 binding to endogenous EphB4 did not influence cell substrate adhesion. Increasing EphB4 expression by transient transfection inhibited cell substrate adhesion, and this effect was also independent of ephrin stimulation because it was not affected by single amino acid mutations in EphB4 that impair ephrin binding. The overexpressed EphB4 was tyrosine phosphorylated, and we found that EphB4 kinase activity is important for inhibition of integrin-mediated adhesion, although several EphB4 tyrosine phosphorylation sites are dispensable. These findings demonstrate that EphB4 can affect cancer cell behaviour in an ephrin-independent manner.

scholarly journals The Novel Methylation Biomarker SCARA5 Sensitizes Cancer Cells to DNA Damage Chemotherapy Drugs in NSCLC

2021 ◽  
Vol 11 ◽  
Author(s):  
Qi Peng ◽  
Yan Liu ◽  
Xuehua Kong ◽  
Jie Xian ◽  
Lin Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Ectopic Expression ◽  
A549 Cells ◽  
Chemotherapeutic Drugs ◽  
Chemotherapy Drugs ◽  
Gene Reporter Assay ◽  
Mechanistic Basis

BackgroundScavenger Receptor Class A Member 5 (SCARA5), also known as TESR, is expressed in various tissues and organs and participates in host defense. Recent studies have found SCARA5 to produce an anti-tumor effect for multiple tumors, although the mechanistic basis for the effect is unknown.MethodsBioinformatics, methylation-specific polymerase chain reaction (MSP), quantitative real-time PCR, and immunohistochemistry were used to assess promoter methylation and expression of SCARA5 in lung cancer tissues and cell lines. The biological effect of SCARA5 on lung cancer cells was confirmed by the CCK8 assay, colony formation assay, and flow cytometry. GSEA, Western blot, RNA sequencing, and luciferase-based gene reporter assay were used to explore the mechanistic basis for the anti-tumor effect of SCARA5. Chemosensitivity assays were used to evaluate the anti-tumor effect of SCARA5 in conjunction with chemotherapeutic drugs.ResultsWe found SCARA5 to be downregulated in lung cancer cell lines and tissues with SCARA5 levels negatively related to promoter methylation. Ectopic expression of SCARA5 suppressed proliferation of lung cancer both in vitro and in vivo through upregulation of HSPA5 expression, which inhibited FOXM1 expression resulting in G2/M arrest of the A549 cell line. SCARA5 also improved susceptibility of A549 cells to chemotherapeutic drugs that damage DNA.ConclusionSCARA5 was silenced in NSCLC due to promoter methylation and could be a potential tumor marker in NSCLC.

Improved Therapeutic Efficacy of Topotecan Against A549 Lung Cancer Cells with Folate-targeted Topotecan Liposomes

2020 ◽  
Vol 21 (11) ◽  
pp. 902-909
Author(s):  
Jingxin Zhang ◽  
Weiyue Shi ◽  
Gangqiang Xue ◽  
Qiang Ma ◽  
Haixin Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Therapeutic Efficacy ◽  
Drug Delivery Systems ◽  
Lung Tumor ◽  
A549 Cells ◽  
Delivery Systems ◽  
Lung Cancer Cells

Background: Among all cancers, lung cancer has high mortality among patients in most of the countries in the world. Targeted delivery of anticancer drugs can significantly reduce the side effects and dramatically improve the effects of the treatment. Folate, a suitable ligand, can be modified to the surface of tumor-selective drug delivery systems because it can selectively bind to the folate receptor, which is highly expressed on the surface of lung tumor cells. Objective: This study aimed to construct a kind of folate-targeted topotecan liposomes for investigating their efficacy and mechanism of action in the treatment of lung cancer in preclinical models. Methods: We conjugated topotecan liposomes with folate, and the liposomes were characterized by particle size, entrapment efficiency, cytotoxicity to A549 cells and in vitro release profile. Technical evaluations were performed on lung cancer A549 cells and xenografted A549 cancer cells in female nude mice, and the pharmacokinetics of the drug were evaluated in female SD rats. Results: The folate-targeted topotecan liposomes were proven to show effectiveness in targeting lung tumors. The anti-tumor effects of these liposomes were demonstrated by the decreased tumor volume and improved therapeutic efficacy. The folate-targeted topotecan liposomes also lengthened the topotecan blood circulation time. Conclusion: The folate-targeted topotecan liposomes are effective drug delivery systems and can be easily modified with folate, enabling the targeted liposomes to deliver topotecan to lung cancer cells and kill them, which could be used as potential carriers for lung chemotherapy.

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.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

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