scholarly journals Receptor functions for the integrin VLA-3: fibronectin, collagen, and laminin binding are differentially influenced by Arg-Gly-Asp peptide and by divalent cations.

1991 ◽  
Vol 112 (1) ◽  
pp. 169-181 ◽  
Author(s):  
M J Elices ◽  
L A Urry ◽  
M E Hemler
Keyword(s):  
Cell Adhesion ◽  
Divalent Cations ◽  
Small Cell Lung Carcinoma ◽  
Rgd Peptide ◽  
Dependent Manner ◽  
Cell Lung Carcinoma ◽  
Ligand Affinity ◽  
Rgd Site ◽  
Inhibition Studies ◽  
Laminin Binding

The capability of the integrin VLA-3 to function as a receptor for collagen (Coll), laminin (Lm), and fibronectin (Fn) was addressed using both whole cell adhesion assays and ligand affinity columns. Analysis of VLA-3-mediated cell adhesion was facilitated by the use of a small cell lung carcinoma line (NCI-H69), which expresses VLA-3 but few other integrins. While VLA-3 interaction with Fn was often low or undetectable in cells having both VLA-3 and VLA-5, NCI-H69 cells readily attached to Fn in a VLA-3-dependent manner. Both Arg-Gly-Asp (RGD) peptide inhibition studies, and Fn fragment affinity columns suggested that VLA-3, like VLA-5, may bind to the RGD site in human Fn. However, unlike Fn, both Coll and Lm supported VLA-3-mediated adhesion that was not inhibited by RGD peptide, and was totally unaffected by the presence of VLA-5. In addition, VLA-3-mediated binding to Fn was low in the presence of Ca++, but was increased 6.6-fold with Mg++, and 30-fold in the presence of Mn++. In contrast, binding to Coll was increased only 1.2-fold with Mg++, and 1.7-fold in Mn++, as compared to the level seen with Ca++. Together, these experiments indicate that VLA-3 can bind Coll, Lm, and Fn, and also show that (a) VLA-3 can recognize both RGD-dependent and RGD-independent ligands, and (b) different VLA-3 ligands have distinctly dissimilar divalent cation sensitivities.

Randomized phase II trial of cisplatin/gemcitabine with or without LY293111, a multiple eicosonaid pathway modulator, in patients with chemotherapy naïve advanced non-small cell lung carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7024-7024
Author(s):  
P. A. Janne ◽  
L. Paz-Ares Rodriguez ◽  
M. Gottfried ◽  
M. N. Reaume ◽  
T. Kaukel ◽  
...  
Keyword(s):  
Phase Ii ◽  
Small Cell Lung Carcinoma ◽  
Stage Iiib ◽  
Type I ◽  
Dependent Manner ◽  
Cell Lung Carcinoma ◽  
Randomized Phase Ii ◽  
Pparγ Agonist ◽  
Significant Difference

7024 Background: The eicosanoid pathway is altered in NSCLC. Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPARγ) have been shown to inhibit lung tumors in vitro. LY293111 inhibits the eicosanoid pathway, is a PPARγ agonist and modulates adipophilin and adiponectin expression levels in vitro. LY293111 is well tolerated and can be administered with cisplatin/gemcitabine. A randomized phase II study in NSCLC was undertaken. Methods: Pts with stage IIIB/IV NSCLC were randomized to two doses of LY293111 (200 mg BID (Arm A) or 600 mg BID (Arm B) or placebo (Arm C) alone for 7 days followed by concurrent cisplatin (75 mg/m2;d1) and gemcitabine (1250 mg/m2;d1,8) q21 days. Treatment was continued until disease progression or toxicity. Primary endpoint was PFS with 75% power to detect 33% improvement compared to placebo (5 months). Calculated sample size was 65 pts/arm (195 total) with a one sided type I error of 0.2. Changes in adipophilin mRNA expression and adiponectin serum levels were assessed at baseline and day 7. Results: Between 09/03 and 07/04, 201 pts were randomized and 195 treated. Demographics (all pts): M:F (65%:35%); median age 61 (range 27–87); stage IIIB/IV (15%:85%); ECOG PS (0:36%;1:64%). Demographics were well balanced between the 3 arms. Most common CTC grade 3/4 toxicities were nausea (8%), vomiting (7%), fatigue (6%) and diarrhea (6%) with only diarrhea related to dose of LY293111 (p=0.03). Response rates (CR+PR) were similar in all 3 arms (A:20%; B:27%; C:21%). There was no significant difference in median PFS (95% CI) between the arms (A: 4.6 months (3.2–5.0); B:6.0 months (4.6–7.2); C:6.0 months (5.2–7.0)). Median survival (95% CI) was similar in all 3 arms (A: 7.3 months (6.2–9.4); B:7.9 months (7.2–9.7); C: 9.0 months (7.7–12.5). Median change in serum adiponectin levels at d7 were significantly higher in arm B vs. placebo (p < 0.05). Adipophilin expression at d7 was increased in a dose dependent manner (p=NS) in arms A and B vs. placebo. Conclusions: LY293111 in combination with cisplatin/gemcitabine did not increase median PFS compared to placebo in pts with NSCLC. Pharmacodynamic modulation was observed but did not impact efficacy. [Table: see text]

scholarly journals O2-sensitive K+ channels in neuroepithelial body-derived small cell carcinoma cells of the human lung

1998 ◽  
Vol 275 (4) ◽  
pp. L709-L716 ◽  
Author(s):  
I. O’Kelly ◽  
C. Peers ◽  
P. J. Kemp
Keyword(s):  
Membrane Potential ◽  
Small Cell Lung Carcinoma ◽  
Acute Hypoxia ◽  
Small Cell ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Cell Lung Carcinoma ◽  
Neuroepithelial Body ◽  
Inward Currents

Neuroepithelial bodies act as airway O2 sensors, but studies of their activity at the cellular level have been severely limited because they are present at such a low density in lung tissue. Small cell lung carcinoma (SCLC) cells are believed to be derived from neuroepithelial body cells and may represent a model system for investigating the mechanisms of airway chemoreception. Here we have used the whole cell patch-clamp technique to investigate the effects of acute hypoxia on voltage-gated ionic currents and membrane potential in H-146 SCLC cells. Step depolarizations evoked transient inward currents due to activation of Na+ and Ca2+ channels, followed by outward K+ currents. K+ currents were partially inhibited by 200 μM Cd2+(indicative of the presence of a Ca2+-dependent component of the K+ current) and were inhibited by tetraethylammonium (TEA) in a concentration-dependent manner, although even at 100 mM TEA, a residual K+current could be detected. Hypoxia ([Formula: see text] 15–20 mmHg) caused a reversible inhibition of outward K+ currents without affecting inward currents. Inhibition by hypoxia was also observed in the presence of Cd2+. Hypoxia and TEA caused membrane depolarization in H-146 cells, and their effects appeared additive. These findings indicate that H-146 cells possess O2-sensitive, Ca2+-independent K+ channels that can influence cell membrane potential. SCLC cells may, therefore, represent a good model for investigating the mechanisms underlying O2 sensing by airway chemoreceptor cells.

scholarly journals Staurosporine Induces the Generation of Polyploid Giant Cancer Cells in Non-Small-Cell Lung Carcinoma A549 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Alexander Glassmann ◽  
Carmen Carrillo Garcia ◽  
Viktor Janzen ◽  
Dominik Kraus ◽  
Nadine Veit ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
A549 Cells ◽  
Small Cell ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Inhibition Of Proliferation ◽  
Polyploid Giant Cancer Cells

Cultivation of A549 non-small-cell lung carcinoma (NSCLC) cells in the presence of staurosporine (SSP) leads to a reduction or a lack of proliferation in a concentration-dependent manner. This inhibition of proliferation is accompanied by the generation of polyploid giant cancer cells (PGCCs) that are characterized by cell flattening, increased cell size, polyploidy, and polynucleation as determined by crystal violet staining, BrdU and DiI labelling, and flow cytometry as well as video time-lapse analysis. Continuous SSP treatment of A549 cells can preserve PGCCs for at least two months in a resting state. Upon removal of SSP, A549 PGCCs restart to divide and exhibit a proliferation pattern and cellular morphology indistinguishable from cells where PGCCs originally derived from. Thus, SSP-treated A549 cells represent a simple and reliable experimental model for the reversible generation of PGCCs and their subsequent experimental analysis.

scholarly journals Flubendazole Elicits Antitumor Effects by Inhibiting STAT3 and Activating Autophagy in Non-small Cell Lung Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaona Xie ◽  
Xueding Cai ◽  
Yemeng Tang ◽  
Chunhui Jiang ◽  
Feng Zhou ◽  
...  
Keyword(s):  
Target Genes ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Autophagic Flux ◽  
Neoplastic Disease ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
Antitumor Effects ◽  
Cell Lung Carcinoma

Non-small cell lung carcinoma (NSCLC) is a major neoplastic disease with a high mortality worldwide; however, effective treatment of this disease remains a challenge. Flubendazole, a traditional anthelmintic drug, possesses potent antitumor properties; however, the detailed molecular mechanism of flubendazole activity in NSCLC needs to be further explored. In the present study, flubendazole was found to exhibit valid antitumor activity in vitro as well as in vivo. Flubendazole blocked phosphorylation of STAT3 in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptotic proteins. Further, flubendazole inhibited STAT3 activation by inhibiting its phosphorylation and nuclear localization induced by interleukin-6 (IL-6). Notably, the autophagic flux of NSCLC cell lines was increased after flubendazole treatment. Furthermore, flubendazole downregulated the expression of BCL2, P62, and phosphorylated-mTOR, but it upregulated LC3-I/II and Beclin-1 expression, which are the main genes associated with autophagy. Collectively, these data contribute to elucidating the efficacy of flubendazole as an anticancer drug, demonstrating its potential as a therapeutic agent via its suppression of STAT3 activity and the activation of autophagy in NSCLC.

Trilinolein Inhibits Proliferation of Human Non-Small Cell Lung Carcinoma A549 Through the Modulation of PI3K/Akt Pathway

2011 ◽  
Vol 39 (04) ◽  
pp. 803-815 ◽  
Author(s):  
Pei-Yu Chou ◽  
Guan-Jhong Huang ◽  
Chun-Hsu Pan ◽  
Yi-Chung Chien ◽  
Ying-Yi Chen ◽  
...  
Keyword(s):  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
A549 Cells ◽  
Panax Notoginseng ◽  
Small Cell ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Proteolytic Activation ◽  
Induced Apoptosis

Trilinolein has been identified as one of the active constituents isolated from Panax notoginseng used widely in traditional Chinese medicine. Protective actions of Panax notoginseng against cerebral ischemia, beneficial effects on the cardiovascular system, and hemostatic, antioxidant, hypolipidemic, hepatoprotective, renoprotective and estrogen-like activities have been illustrated. In the present study, the effects of trilinolein on the growth of non-small cell lung carcinoma A549 were investigated. It was found that the exposure of A549 cells to trilinolein resulted in the growth inhibition and the induction of apoptosis in a dose- and time- dependent manner. Trilinolein treatment induced the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 expression, which was associated with the proteolytic activation of caspases and the concomitant degradation of poly(ADP-ribose) polymerase (PARP) protein. Intracellular reactive oxygen species seem to play a role in the trilinolein-induced apoptosis, since ROS were produced early in the trilinolein treatment. Moreover, the activity of PI3K/Akt was downregulated in trilinolein-treated cells. Our results demonstrated that the most important regulators of trilinolein-induced apoptosis are Bcl-2 family and caspase-3, which are associated with cytochrome c release and dephosphorylation on the Akt signaling pathway.

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