Licochalcone A Inhibits the Proliferation of Human Lung Cancer Cell Lines A549 and H460 by Inducing G2/M Cell Cycle Arrest and ER Stress

Qiu, Chenyu; Zhang, Tingting; Zhang, Wenxin; Zhou, Lina; Yu, Bin; Wang, Wei; Yang, Zhihong; Liu, Zhiguo; Zou, Peng; Liang, Guang

doi:10.3390/ijms18081761

Cited by 78 publications

(66 citation statements)

References 34 publications

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“…LCD decreased cyclin B1/cdc2 protein expression but increased CKI, causing G2/M cell cycle arrest. LCA and LCB of the same licorice family as LCD can also block G2/M cell cycle progression and induce the apoptosis of lung cancer cells [14,24]. Some agents that can induce apoptosis may also increase cytotoxicity in association with G2/M checkpoint arrest [23].…”

Section: Discussionmentioning

confidence: 99%

Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET

Lee

Kim

et al. 2020

Biomolecules

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Licochalcone D (LCD), a flavonoid isolated from a Chinese medicinal plant Glycyrrhiza inflata, has a variety of pharmacological activities. However, the anti-cancer effects of LCD on non-small cell lung cancer (NSCLC) have not been investigated yet. The amplification of MET (hepatocyte growth factor receptor) compensates for the inhibition of epidermal growth factor receptor (EGFR) activity due to tyrosine kinase inhibitor (TKI), leading to TKI resistance. Therefore, EGFR and MET can be attractive targets for lung cancer. We investigated the anti-proliferative and apoptotic effects of LCD in lung cancer cells HCC827 (gefitinib-sensitive) and HCC827GR (gefitinib-resistant) through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, pull-down/kinase assay, cell cycle analysis, Annexin-V/7-ADD staining, reactive oxygen species (ROS) assay, mitochondrial membrane potential (MMP) assay, multi-caspase assay, and Western blot analysis. The results showed that LCD inhibited phosphorylation and the kinase activity of EGFR and MET. In addition, the predicted pose of LCD was competitively located at the ATP binding site. LCD suppressed lung cancer cells growth by blocking cell cycle progression at the G2/M transition and inducing apoptosis. LCD also induced caspases activation and poly (ADP-ribose) polymerase (PARP) cleavage, thus displaying features of apoptotic signals. These results provide evidence that LCD has anti-tumor effects by inhibiting EGFR and MET activities and inducing ROS-dependent apoptosis in NSCLC, suggesting that LCD has the potential to treat lung cancer.

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Section: Discussionmentioning

confidence: 99%

Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET

Lee

Kim

et al. 2020

Biomolecules

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“…It is well known that the core of the cell cycle regulation mechanism is a group of cell cycle dependent protein kinase (CDKs), which is dependent on their regulatory subunit cyclins. Cyclin E and CDK2 are major regulators of cell cycle checkpoint and their interaction triggers the entry into the S phase, while cyclin B1‐CDK1 is potential to promote cell cycle progression from the S phase to G 2 /M phase . ADP has been reported to inhibit proliferation of the human lung adenocarcinoma cells via the induction of massive accumulation of cells in the S phase .…”

Section: Discussionmentioning

confidence: 99%

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

Chen

Xiao

Yang

et al. 2018

J of Cellular Biochemistry

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Extracellular adenosine diphosphate (ADP) mediates a wide range of physiological effects as an extracellular signaling molecule, including platelet aggregation, vascular tone, cell proliferation, and apoptosis by interacting with plasma membrane P2 receptors. However, the effect of ADP on cell proliferation was contradictory. In this study, we found that ADP significantly inhibited cell proliferation of human umbilical vein endothelial cells at high concentrations (50 to 100 µM). Treatment with ADP did not induce cell apoptosis but instead induced cell cycle arrest in the S phase, which may be partly due to the downregulation of cyclin B1. The inhibition of cell proliferation was blocked by suramin, a nonspecific antagonist of the P2 receptors, and high concentrations of ADP significantly upregulated the messenger RNA (mRNA) and protein expression of P2Y11 in endothelial cells. Moreover, the downregulation of P2Y11 by RNA interference reversed the inhibition of cell proliferation. In addition, ADP (100 µM) can induce the formation of cytosolic autophagy in endothelial cells and a rapid phosphorylation of extracellular signal regulated kinase (ERK) 1/2, which is a canonical signal molecule downstream of P2Y receptors, accompanied by a mRNA expression of proinflammatory cytokines such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Taken together, our study excludes a mechanism for extracellular ADP impairing endothelial cells proliferation via P2Y11 receptor by downregulating cyclin B1 and arresting cell cycle at the S phase, besides, ADP induces cell autophagy and mRNA expression of inflammatory cytokines, whether it is mediated by Erk signaling pathways needs further studies to confirm.

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“…Recent studies have reported that licorice roots contain multiple bioactive components such as saponins, flavonoids, and coumarins [13][14][15]. Furthermore, licorice has been shown to have anticancer effects in various types of cancer such as colon [16], lung [17,18], breast [19,20], prostate [21], and oral cancers [11] through metastatic inhibition [19], anti-proliferative properties [20], increased apoptosis [11,22], and cell cycle arrest [23].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recent studies have also reported reduction in chronic allergic contact dermatitis as well as antidiabetic, anti-inflammatory, and antimicrobial effects. Anticancer effects of Lico-A have been prominently reported for various types of cancers, such as A549 and H460 human lung cancer cells [17], T24 bladder cancer cells [31], human cervical cancer cells [32], human BGC-823 gastric cancer cells [33], malignant pleural mesothelioma [34], human FaDu head and neck squamous carcinoma cells [22], and human esophageal carcinoma [35] among others. On the other hand, although recent studies associated with the biological effects of Lico-E have been reported antidiabetic effect [36], the reduction of chronic allergic contact dermatitis [37], neuronal protection [38], anti-inflammation [39] and antimicrobial effects [40], but the anticancer effects of Lico-E reported in the 4T1 mammary orthotopic cancer [41] and human head and neck squamous carcinoma FaDu cells [11].…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of licochalcone-E is mediated by caspase-dependent apoptosis through extrinsic and intrinsic apoptotic signaling pathways in KB cancer cells

et al. 2017

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·············································································································································································This study investigates the anti-cancer effects of licochalcone-E (Lico-E), a phenolic chalconoid derived from the genus Glycyrrhiza, in the human KB squamous cancer cell. Concentration-dependent cytotoxicity in KB cells increased following 24 hours of treatment with 12.5, 25, or 50 µg/ml Lico-E, with an estimated IC 5 0value of approximately 25 µg/ml. Chromatin condensation, a typical apoptotic phenomenon, was observed in KB cells treated with Lico-E. Consistent with this finding, Lico-E increased caspase-3 activity in KB cells. FasL, a death ligand associated with extrinsic apoptotic signaling pathways, was significantly up-regulated by Lico-E treatment. Subsequently, the pro-apoptotic factor caspase-8, a part of the extrinsic apoptotic signaling pathway, was activated in a concentrationdependent manner by Lico-E treatments. Expression of anti-apoptotic factors such as Bcl-2 and Bcl-xL, components of the mitochondriadependent apoptotic signaling pathway, significantly decreased following Lico-E treatment. Conversely, expression of pro-apoptotic factors such as Bax, Bad, Apaf-1, and caspase-9 increased with Lico-E concentrations. Finally, Lico-E activated caspase-3 and Poly (ADP-ribose) polymerase (PARP) to induce cell death. Z-VAD-fmk significantly inhibited cell death through suppression of caspase-3 expression in KB cells treated with Lico-E. Taken together, Lico-E induces KB cell death through death receptor and mitochondriadependent apoptotic signaling pathways.

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Licochalcone A Inhibits the Proliferation of Human Lung Cancer Cell Lines A549 and H460 by Inducing G2/M Cell Cycle Arrest and ER Stress

Cited by 78 publications

References 34 publications

Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET

Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

Anti-tumor effect of licochalcone-E is mediated by caspase-dependent apoptosis through extrinsic and intrinsic apoptotic signaling pathways in KB cancer cells

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