Novel focal adhesion kinase 1 inhibitor sensitizes lung cancer cells to radiation in a p53-independent manner

Jung, Seung‐Hyun; Kho, Seongho; Song, Kyung-Hee; Ahn, Joon-Woo; Park, In-Chul; Nam, Ky-Youb; Hwang, Sang‐Gu; Nam, Seon-Young; Cho, Seong‐Jun; Song, Jie‐Young

doi:10.3892/ijo.2017.4141

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…4A, combined treatment with PPA15 and irradiation significantly increased the population of annexin-positive cells in a p53independent manner. It is well known that p53 and p21 are key regulators of cell cycle arrest and apoptosis, and that both are involved in G 1 as well as G 2 /M arrest after irradiation, thereby sensitizing tumor cells to radiation (Iliakis et al, 2003;Jung et al, 2017). As expected, irradiation markedly increased the protein levels of p53 and p21 in p53 wild-type A549 cells, whereas PPA15 did not significantly alter p53/p21 levels, but rather increased the levels of PARP1 cleavage and gH2AX expression.…”

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confidence: 60%

Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation

Jung¹,

Nam²,

Park³

et al. 2019

J Pharmacol Exp Ther

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Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N-phenylpyrimidin-2-amine (PPA) lead compound. In the present study, 17 derivatives of this lead compound were examined, and it was found that 4-(4-fluorophenyl)-N-(4-nitrophenyl)-6-phenylpyrimidin-2-amine (PPA5), 4-((4-(4fluorophenyl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl-benzamide (PPA13), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA14), 4-((4-(2-chlorophenyl)pyrimidin-2-yl) amino)benzenesulfonamide (PPA15), and 4-((4-(2-chlorophenyl) pyrimidin-2-yl)amino)-N-methylbenzamide (PPA17) inhibited cell viability by more than 50%, with a marked increase in the proportion of cells arrested at the G 2 /M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G 1 cell population and increased the levels of cyclin B1 and the phosphorylation levels of cyclin-dependent kinase (CDK) 1. Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, respectively. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer. SIGNIFICANCE STATEMENT Several inhibitors of CDK have been successfully evaluated in combination with other chemotherapeutics in clinical trials, but negative side effects have partially restricted their clinical use. In this study, we identified a novel pan-CDK inhibitor to increase radiosensitivity, and we hope this work will encourage the development of promising small-molecule radiosensitizers.

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Section: Downloaded Fromsupporting

confidence: 60%

Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation

Jung¹,

Nam²,

Park³

et al. 2019

J Pharmacol Exp Ther

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“…Efforts to search for its candidate receptors are underway. Currently, FAK inhibitors are mostly used in the treatment of cancer, 36 , 37 , 38 , 39 and a few are used for the treatment of other diseases, such as liver and lung fibrosis. 40 , 41 In this study, we observed the unique role that C1QTNF4‐mediated downregulation of the FAK/PI3K/AKT pathway plays in reducing the abnormal proliferation and migration of VSMCs.…”

Section: Discussionmentioning

confidence: 99%

C1q/TNF‐related protein 4 mediates proliferation and migration of vascular smooth muscle cells during vascular remodelling

Liu

Long

et al. 2023

Clinical & Translational Med

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Background Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually results in major adverse cardiovascular events. The C1q/TNF‐related protein (C1QTNF) family is closely associated with cardiovascular disease. Notably, C1QTNF4 has unique two C1q domains. However, the role of C1QTNF4 in vascular diseases remains unclear. Methods C1QTNF4 expression was detected in human serum and artery tissues using ELISA and multiplex immunofluorescence (mIF) staining. Scratch assay, transwell assay and confocal microscopy were used to investigate C1QTNF4 effects on VSMC migration. EdU incorporation, MTT assay and cell counting experiment revealed C1QTNF4 effects on VSMC proliferation. C1QTNF4‐transgenic, C1QTNF4−/− and AAV9‐mediated VSMC‐specific C1QTNF4 restoration C1QTNF4−/‐ mouse and rat disease models were generated. RNA‐seq, quantitative real‐time PCR, western blot, mIF, proliferation and migration assays were used to investigate the phenotypic characteristics and underlying mechanisms. Results Serum C1QTNF4 levels were decreased in patients with arterial stenosis. C1QTNF4 shows colocalisation with VSMC in human renal arteries. In vitro, C1QTNF4 inhibits VSMC proliferation and migration and alters VSMC phenotype. In vivo, an adenovirus‐infected rat balloon injury model, C1QTNF4‐transgenic and C1QTNF4−/− mouse wire‐injury models with or without VSMC‐specific C1QTNF4 restoration were established to mimic the VSMC repair and remodelling. The results show that C1QTNF4 decreases intimal hyperplasia. Especially, we displayed the rescue effect of C1QTNF4 in vascular remodelling using AAV vectors. Next, transcriptome analysis of artery tissue identified the potential mechanism. In vitro and in vivo experiments confirm that C1QTNF4 ameliorates neointimal formation and maintains vascular morphology by downregulating the FAK/PI3K/AKT pathway. Conclusions Our study demonstrated that C1QTNF4 is a novel inhibitor of VSMC proliferation and migration that acts by downregulating the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation. These results provide new insights into promising potent treatments for vascular stenosis diseases.

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Palbociclib induces DNA damage and inhibits DNA repair to induce cellular senescence and apoptosis in oral squamous cell carcinoma

Wang

Leu

Lee

et al. 2021

Journal of the Formosan Medical Association

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Novel focal adhesion kinase 1 inhibitor sensitizes lung cancer cells to radiation in a p53-independent manner

Cited by 3 publications

References 37 publications

Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation

Radiosensitizing Effect of Novel Phenylpyrimidine Derivatives on Human Lung Cancer Cells via Cell Cycle Perturbation

C1q/TNF‐related protein 4 mediates proliferation and migration of vascular smooth muscle cells during vascular remodelling

Palbociclib induces DNA damage and inhibits DNA repair to induce cellular senescence and apoptosis in oral squamous cell carcinoma

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