A novel nitric oxide-donor-ferulic acid hybrid inhibits proliferation and metastasis of human lung cancer A549 cells via regulation of multiple signaling pathways

2019 ◽  
Author(s):  
Shi-Jun Yue ◽  
Peng-Xuan Zhang ◽  
Yue Zhu ◽  
Nian-Guang Li ◽  
Yan-Yan Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathways ◽  
Human Lung ◽  
A549 Cells ◽  
Mitogen Activated Protein Kinase ◽  
Human Lung Cancer ◽  
No Donor ◽  
Anti Cancer ◽  
Mitogen Activated Protein ◽  
Proliferation And Metastasis

Lung cancer is one of the most common malignancies as well as an increasing cause of cancer-related deaths. Nitric oxide (NO)-donor-ferulic acid (FA) hybrids, in our previous study, were designed and synthesized, which exhibited positive anti-cancer activities, especially one compound labelled as FXS-3. In this study, an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed and revealed the inhibitory effect of FXS-3 on the proliferation and metastasis of human lung cancer A549 cells. The further flow cytometry assay showed that FXS-3 induced apoptosis of A549 cells by inducing cell cycle arrest at the G0/G1 phase. The trans-well migration and Matrigel invasion assays revealed that FXS-3 inhibited the migration and invasion of A549 cells. By the western blotting analysis, FXS-3 increased the expression of B-cell lymphoma-2 (Bcl-2) associated X protein (Bax)/Bcl-2 ratio, inhibited matrix metalloproteinase (MMP)-2 and MMP-9, and suppressed the mitogen-activated protein kinase (MAPK), AKT/mechanistic target of rapamycin (mTOR), as well as mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. The subsequent A549 xenograft-bearing mouse model and tail vein injection of A549 cells induced pulmonary tumor metastasis model showed that FXS-3 significantly restrained the tumor growth and metastasis. In conclusion, FXS-3 might inhibit proliferation and metastasis of human lung cancer A549 cells by inhibiting MAPK, AKT/mTOR and MEK/ERK signaling pathways, which provides important scientific basis for the development of anti-cancer drugs about NO-donor-FA hybrids.

scholarly journals A Ferulic Acid Derivative FXS-3 Inhibits Proliferation and Metastasis of Human Lung Cancer A549 Cells via Positive JNK Signaling Pathway and Negative ERK/p38, AKT/mTOR and MEK/ERK Signaling Pathways

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2165 ◽  
Author(s):  
Shi-Jun Yue ◽  
Peng-Xuan Zhang ◽  
Yue Zhu ◽  
Nian-Guang Li ◽  
Yan-Yan Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathways ◽  
Human Lung ◽  
A549 Cells ◽  
Erk Signaling ◽  
Human Lung Cancer ◽  
Jnk Signaling ◽  
Anti Cancer ◽  
Proliferation And Metastasis ◽  
Jnk Signaling Pathway

Lung cancer is one of the most common malignancies and is an increasing cause of cancer-related deaths. In our previous study, a series of ferulic acid (FA) derivatives were designed and synthesized; they exhibited positive anti-cancer activities, especially for a compound labelled FXS-3. In this study, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed, wherein it revealed the inhibitory effect of FXS-3 on the proliferation and metastasis of human lung cancer A549 cells. The further flow cytometry assay showed that FXS-3 induced apoptosis of A549 cells induced cell cycle arrest at the G0/G1 phase. The trans-well migration and Matrigel invasion assays revealed that FXS-3 inhibited the migration and invasion of A549 cells. By the western blotting analysis, FXS-3 increased the expression of B-cell lymphoma-2 (Bcl-2) associated X protein (Bax)/Bcl-2 ratio, inhibited matrix metalloproteinase (MMP)-2 and MMP-9, and regulated the extracellular signal-regulated kinase (ERK)/p38, c-Jun N-terminal kinase (JNK), protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), as well as mitogen-activated protein kinase (MEK)/ERK signaling pathways. The subsequent A549 xenograft-bearing mouse model and tail vein injection of A549 cells induced pulmonary tumor metastasis model showed that FXS-3 significantly restrained the tumor growth and metastasis. In conclusion, FXS-3 might inhibit proliferation and metastasis of human lung cancer A549 cells by positively regulating JNK signaling pathway and negativly regulating ERK/p38, AKT/mTOR, and MEK/ERK signaling pathways, which provides important scientific basis for the development of anti-cancer drugs about FA derivatives.

scholarly journals Kaempferide Induces G0/G1 Phase Arrest and Apoptosis via ROS-Mediated Signaling Pathways in A549 Human Lung Cancer Cells

2020 ◽  
Vol 15 (7) ◽  
pp. 1934578X2093522
Author(s):  
Hong-Liang Li ◽  
Shu-Mei Li ◽  
Ying-Hua Luo ◽  
Wan-Ting Xu ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Signaling Pathways ◽  
Cell Apoptosis ◽  
Human Lung ◽  
A549 Cells ◽  
Human Lung Cancer ◽  
Expression Levels ◽  
Cycle Arrest ◽  
Human Lung Cancer Cells

Kaempferide is an O-methylated flavonol that has received much attention due to its various biological activities. In this study, we explored the underlying mechanisms of kaempferide in human lung cancer A549 cells. The Cell Counting Kit-8 (CCK-8) assay, Hoechst 33342/propidium iodide double staining, flow cytometry, scratch wound healing assay, and Western blot analysis were used to measure cell apoptosis, the cell cycle, reactive oxygen species (ROS) levels, and cell migration of human lung cancer cells. Kaempferide significantly inhibited human lung cancer cell proliferation, and its toxic effects on normal cells were significantly lower than those of 5-fluorouracil. Kaempferide induced A549 cell apoptosis by decreasing the mitochondrial membrane potential and the expression level of B-cell lymphoma 2, and by increasing the expression levels of Bcl-2-associated X protein and caspase-3. It also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling pathways by increasing the expression levels of phosphorylated c-Jun N-terminal kinase, p-p38, I kappa B, and by decreasing the expression levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, and NF-κB. Kaempferide induced cell cycle arrest in the G0/G1 phase in A549 cells by downregulating the expression levels of p-AKT, cyclin D1, and cyclin-dependent kinase 2. Furthermore, kaempferide blocked A549 cell migration by downregulating the expression levels of transforming growth factor beta 1 (TGF-β1), p-β-catenin, p-glycogen synthase kinase 3 beta, N-cadherin, and vimentin, and by upregulating the expression level of E-cadherin. Kaempferide enhanced the accumulation of ROS, and N-acetyl-l-cysteine (a ROS inhibitor) decreased the regulation of MAPK, NF-κB, AKT, and TGF-β signaling pathways by kaempferide, inhibited cell apoptosis, and reversed cell cycle arrest. Our results showed that kaempferide induced apoptosis via ROS-mediated MAPK, NF-κB, AKT, and TGF-β signaling pathways in A549 cells. Thus, kaempferide may be a novel drug candidate for lung cancer.

Beneficial Effects Of Ionizing Radiation To Enhance Anti-Cancer Effects Of RIG-Like Receptor Stimulus

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4721-4721
Author(s):  
Hironori Yoshino ◽  
Ikuo Kashiwakura
Keyword(s):  
Lung Cancer ◽  
Ionizing Radiation ◽  
Human Lung ◽  
A549 Cells ◽  
Annexin V ◽  
Poly I:C ◽  
Human Lung Cancer ◽  
Tnf Α ◽  
Significant Difference ◽  
Anti Cancer

Introduction The immune system is composed of innate and adaptive immunity. Antigen presenting cells (APCs), such as macrophages and dendritic cells, serve as a link between innate and adaptive immunity. Furthermore, APCs express pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns. Retinoic acid-inducible gene-I (RIG-I)-like receptors [RLRs; RIG-I and melanoma differentiation-associated gene 5 (MDA5)] are a type of PRRs and sense virus-derived RNA or a synthetic analog of dsRNA polyinosinic-polycytidylic acid [poly(I:C)]. Although macrophages are resistant to ionizing radiation, it remains unclear whether radiation affects RLR expression in the macrophages. Therefore, the effects of ionizing radiation on the RLR expression in macrophages and the response against poly(I:C) were herein investigated. Additionally, the anti-cancer effects of poly(I:C) and the combination treatment of poly(I:C) with ionizing radiation was examined in human lung cancer A549 cells. Methods For preparation of human macrophage-like cells, the human acute monocytic leukemia THP1 cells were treated with phorbol 12-myristate 13-acetate and then differentiated into macrophage-like cells. To stimulate RLRs, poly(I:C)/LyoVecTM (InvivoGen), which is a complex between poly(I:C) and the transfection reagent LyoVecTM, was used on macrophage-like differentiated THP-1 cells. X-irradiation was performed with an X-ray generator at a dose rate of 102.0–104.0 cGy/min. The viable cells were counted by trypan blue exclusion assay. The expression of RLRs was analyzed by reverse transcription polymerase chain reaction (RT-PCR) or western blotting. The interferon (IFN)-β expression and tumor necrosis factor (TNF)-α concentration present in culture supernatants were analyzed by RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. The cell death analysis was performed by fluorescein isothiocyanate labeled annexin V and propidium iodide (PI) staining and analyzed by flow cytometry. Results The effects of ionizing radiation on RLR expression were first investigated. Both non-irradiated and X-irradiated (1–10 Gy) macrophage-like cells expressed RIG-I and MDA-5, with no significant difference in expression levels. Next the response of macrophage-like cells to poly(I:C)/LyoVecTM (500 ng/ml) was examined. Although the expression of IFN-β was not observed in non-stimulated macrophage-like cells, the poly(I:C)/LyoVecTM-stimulated macrophage-like cells expressed IFN-β. In X-irradiated macrophage-like cells, IFN-β expression after poly(I:C)/LyoVecTM stimulation was comparable with that of non-irradiated cells. Similar to the IFN-β expression, no significant difference in concentration of TNF-α were observed after poly(I:C)/LyoVecTMstimulation in non-irradiated and irradiated cells. These results suggest that ionizing radiation did not affect RLR expression or the response against poly(I:C) in macrophages. We next investigated the anti-cancer effects of poly(I:C)/LyoVecTM against human lung cancer A549 cells. Treatment with poly(I:C)/LyoVecTM (500 and 1000 ng/ml) suppressed the A549 cell growth (approximately 70% and 80% inhibition, respectively). Furthermore, the treatment with poly(I:C)/LyoVecTM induced both annexin V(+)/PI(−) (early apoptotic cells) and annexin V(+)/PI(+) cells (late apoptotic/necrotic cells). Finally, the combination treatment of poly(I:C) with 2 Gy was tested. The cell growth suppressive effects of 2 Gy resulted in 30% inhibition, whereas the combination of 2 Gy with poly(I:C)/LyoVecTM (500 and 1000 ng/ml) resulted in 85% and 90% inhibition, respectively. Correspondingly, the proportion of early apoptotic cells and late apoptotic/necrotic cells were higher in the combination of 2 Gy with poly(I:C)/LyoVecTM compared with 2 Gy alone or poly(I:C)/LyoVecTMalone. These results suggest that poly(I:C) and ionizing radiation synergistically exhibit anti-cancer effects against A549 cells. Conclusion This study demonstrated that ionizing radiation synergistically acted with RLR stimulation in suppressing the growth of human lung cancer cells without affecting the expression of RLRs in macrophages. Therefore, the combination of radiation therapy with RLR stimulus is expected to be an effective cancer therapy. Disclosures: No relevant conflicts of interest to declare.

Cochinchina MomordicaSeed Suppresses Proliferation and Metastasis in Human Lung Cancer Cells by Regulating Multiple Molecular Targets

2015 ◽  
Vol 43 (01) ◽  
pp. 149-166 ◽  
Author(s):  
Yang Shen ◽  
Linyi Meng ◽  
Huajun Sun ◽  
Yizhun Zhu ◽  
Hongrui Liu
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
A549 Cells ◽  
Molecular Targets ◽  
Human Lung Cancer ◽  
Migration And Invasion ◽  
Human Lung Cancer Cells ◽  
Proliferation And Metastasis ◽  
Specific Inhibitors

Cochinchina Momordica Seed, which is the dried ripe seed of Momordica cochinchinensis (Lour.) Spreng, has been used as a mainly anticancer ingredient for many years in China. This study aims at investigating the roles of an ethanol-soluble extract of Cochinchina Momordica Seed (ECMS) in suppressing the proliferation and metastasis of human lung cancer cells, and further elucidating underlying molecular mechanisms. Our researches suggest that ECMS dose-dependently decreased the survival rates of A549 and H1299 cells, and inhibited the migration and invasion in A549 cells. ECMS-induced apoptosis was accompanied by up-regulation of p53, Bax and the down-regulation of Bcl-2, PI-3K/Akt signal pathway, and resulted in the dissipation of mitochondrial membrane potential (ΔΨm) and sequentially activated caspase-3 cascade. Pre-treated with specific inhibitors, LY294002 (PI-3K inhibitor) and BAY11-7082 (NF-κB inhibitor) could enhance the anti-proliferation effects of ECMS on A549 cells. Furthermore, ECMS could increase the level of E-cadherin and decrease of the level of STAT-3 and MMP-2, and scarcely affected the expression of VEGF, and resulted in the inhibition of migration and invasion. Pre-treated with specific inhibitors, WP1066 (STAT-3 inhibitor) and TIMP-2 (MMP-2 inhibitor) could enhance the inhibitory effects of ECMS on migration. In conclusion, the current data demonstrated ECMS inhibited the proliferation of A549 cells by inducing apoptosis, at least partly through the activation of p53 and inactivation of PI-3K/Akt signaling. STAT-3 and MMP-2 pathways may be partly involved in anti-metastasis activities of ECMS. Hence, ECMS might be a promising candidate for the therapy of the non-small cell lung cancer by regulating multiple molecular targets.

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