Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

Zhang, Jianli; Hong, Yu; Shen, Jie

doi:10.1007/s13277-015-3244-2

Cited by 19 publications

(17 citation statements)

References 38 publications

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“…A549 cells express wild type EGFR that is important for A549 cell growth [40]. Concomitant inhibition of AKT and ERK1/2 synergistically inhibits A549 cell growth and induces apoptosis in vitro and in vivo [24,41,42]. In agreement with these findings, YXQ-EQ induced apoptosis was associated with dual inhibition of AKT and ERK1/2 activation in A549 cells.…”

Section: Discussionmentioning

confidence: 54%

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells

Yan¹,

Shen²,

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer is one of the most prevalent malignancies in the world. The 5-year survival rate for non-small cell lung cancer (NSCLC) patients is only approximately 15%, with metastasis as the primary cause of death. This study was aimed to investigate cytotoxic effect of external qi of Yan Xin Qigong (YXQ-EQ) toward human lung adenocarcinoma A549 cells as well as its effect on signaling pathways promoting migration, invasion and epithelial-to-mesenchymal transition (EMT) in A549 cells. Methods: Cytotoxic effect of YXQ-EQ was evaluated using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] and cologenic assays. Apoptosis of treated cells was determined by Annexin V/propidium iodide staining and flow cytometry analysis, while cell migration and invasion were determined using transwell assays and EMT was assessed by morphological changes in cells. Protein expression and phosphorylation were examined by immunoblot analyses. Results: YXQ-EQ induced apoptosis in A549 cells, resulting in a pronounced reduction in viability and clonogenic formation. This was associated with inhibition of phosphorylation of AKT and ERK1/2 and reduced expression of anti-apoptotic proteins BCL-xL, XIAP and survivin. Furthermore, YXQ-EQ inhibited EGF/EGFR signaling and EGF mediated migration and invasion of A549 cells. While TGF-β1 induced phosphorylation of SMAD2/3 and EMT in A549 cells, YXQ-EQ suppressed TGF-β/SMAD signaling and induced cell death in these cells in the presence of TGF-β1. Conclusion: Our findings suggest that YXQ-EQ could exert anti-lung cancer effects via inhibiting signaling pathways that are important for NSCLC cell survival and NSCLC metastasis.

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Section: Discussionmentioning

confidence: 54%

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells

Yan¹,

Shen²,

Jiang

et al. 2018

Cell Physiol Biochem

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“…Mechanisms involved in the action of perifosine include interference with the activation of Akt [1-4, 6, 8-13, 15, 16, 18, 20, 21] and stimulation of death receptor clustering [3, 22] with subsequent triggering of suicidal cell death or apoptosis [3, 8, 11-14, 16-18, 21, 23]. On the other hand, perifosine could activate AMP activated kinase AMPK and protect against cell death [24].…”

Section: Introductionmentioning

confidence: 99%

Triggering of Eryptosis, the Suicidal Erythrocyte Death, by Perifosine

Egler

Läng²

2017

Cell Physiol Biochem

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Background/Aims: The alkylphospholipid perifosine is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. Side effects of perifosine include anemia. At least in theory, perifosine-induced anemia could result from stimulation of suicidal erythrocyte death or eryptosis. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms participating in the orchestration of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress, increase of ceramide abundance, as well as activation of staurosporine sensitive protein kinase C and/or of SB203580 sensitive p38 kinase. The present study explored, whether perifosine induces eryptosis and, if so, whether its effect involves and/or requires Ca²⁺ entry, oxidative stress, ceramide and kinase activation. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. Results: A 24 hours exposure of human erythrocytes to perifosine (2.5 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased average forward scatter, significantly increased the percentage of shrunken erythrocytes, and significantly decreased the percentage of swollen erythrocytes. Perifosine significantly increased the percentage of hemolytic erythrocytes. Perifosine significantly increased Fluo3-fluorescence, but decreased DCFDA fluorescence and ceramide abundance. The effect of perifosine on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺ and by addition of staurosporine (1 µM), but not by addition of SB203580 (2 µM). Conclusions: Perifosine triggers eryptosis, an effect at least in part due to Ca²⁺ entry and activation of staurosporine sensitive kinases.

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“…The combination of MEK162 and imatinib (Gleevec), a tyrosine kinase inhibitor, synergistically suppresses the growth of gastrointestinal stromal tumor in vitro and in vivo [6]. The combination of MEK162 and perifosine, an Akt inhibitor, synergistically inhibits the growth of lung cancer cells in vitro and in vivo [7]. In the clinic, MEK162 has shown some activity in patients with N-Ras-mutated melanoma [8].…”

Section: Introductionmentioning

confidence: 99%

Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells

et al. 2015

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Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK-targeted therapy. The current study focuses on demonstrating the activity of MEK162, a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it induces autophagy and accordingly the combination of MEK162 with the autophagy inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120, a pan PI3K inhibitor, abrogates induced Akt activation and significantly augments therapeutic efficacy against the growth of NSCLC cells both in vitro and in vivo. Hence our findings warrant further evaluation of these rational combinations in the clinic.

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Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

Cited by 19 publications

References 38 publications

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells

Triggering of Eryptosis, the Suicidal Erythrocyte Death, by Perifosine

Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells

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