Hydroxyl Group Difference between Anthraquinone Derivatives Regulate Different Cell Death Pathways via Nucleo-Cytoplasmic Shuttling of p53

Background: Despite a number of measures having been taken for cancer management, it is still the second leading cause of death worldwide. p53 is the protein principally being targeted for cancer treatment. Targeting p53 localization may be an effective strategy in chemotherapy as it controls major cell death pathways based on its cellular localization. Anthraquinones are bioactive compounds widely being considered as potential anticancer agents but their mechanism of action is yet to be explored. It has been shown that the number and position of hydroxyl groups within the different anthraquinones like Emodin and Chrysophanol reflects the number of intermolecular hydrogen bonds which affect its activity. Emodin contains an additional OH group at C-3, in comparison to Chrysophanol and may differentially regulate different cell death pathways in cancer cell. Objective: The present study was aimed to investigate the effect of two anthraquinones Emodin and Chrysophanol on induction of different cell death pathways in human lung cancer cells (A549 cell line) and whether single OH group difference between these compounds differentially regulate cell death pathways. Methods: The cytotoxic effect of Emodin and Chrysophanol was determined by the MTT assay. The expression of autophagy and apoptosis marker genes at mRNA and protein level after treatment was checked by the RT-PCR and Western Blot, respectively. For cellular localization of p53 after treatment, we performed immunofluorescence microscopy. Results: We observed that both compounds depicted a dose-dependent cytotoxic response in A549 cells which was in concurrence with the markers associated with oxidative stress such as an increase in ROS generation, decrease in MMP and DNA damage. We also observed that both compounds up-regulated the p53 expression where Emodin causes nuclear p53 localization, which leads to down-regulation in mTOR expression and induces autophagy while Chrysophanol inhibits p53 translocation into nucleus, up-regulates mTOR expression and inhibits autophagy. Conclusion: From this study, it may be concluded that the structural difference of single hydroxyl group may switch the mechanism from one pathway to another which could be useful in the future to improve anticancer treatment and help in the development of new selective therapies.

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The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Cancers ◽

10.3390/cancers11091313 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1313

Author(s):

Man Wang ◽

Shuai Jiang ◽

Yinfeng Zhang ◽

Peifeng Li ◽

Kun Wang

Keyword(s):

Cell Death ◽

Biological Significance ◽

Chemotherapeutic Agents ◽

The Body ◽

Cell Swelling ◽

Pathogen Invasion ◽

Membrane Rupture ◽

Cancer Management ◽

Cell Death Pathways ◽

Cancer Pathogenesis

Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

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Houttuynia cordata Thunb extract modulates G0/G1 arrest and Fas/CD95-mediated death receptor apoptotic cell death in human lung cancer A549 cells

Journal of Biomedical Science ◽

10.1186/1423-0127-20-18 ◽

2013 ◽

Vol 20 (1) ◽

pp. 18 ◽

Cited By ~ 18

Author(s):

Yuh-Fung Chen ◽

Jai-Sing Yang ◽

Wen-Shin Chang ◽

Shih-Chang Tsai ◽

Shu-Fen Peng ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Human Lung ◽

Apoptotic Cell ◽

Death Receptor ◽

A549 Cells ◽

Human Lung Cancer ◽

G1 Arrest ◽

Houttuynia Cordata ◽

Houttuynia Cordata Thunb

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Sea Hare Hydrolysate-Induced Reduction of Human Non-Small Cell Lung Cancer Cell Growth through Regulation of Macrophage Polarization and Non-Apoptotic Regulated Cell Death Pathways

Cancers ◽

10.3390/cancers12030726 ◽

2020 ◽

Vol 12 (3) ◽

pp. 726 ◽

Cited By ~ 1

Author(s):

Marie Merci Nyiramana ◽

Soo Buem Cho ◽

Eun-Jin Kim ◽

Min Jun Kim ◽

Ji Hyeon Ryu ◽

...

Keyword(s):

Cell Death ◽

Macrophage Activation ◽

Macrophage Polarization ◽

A549 Cells ◽

Small Cell ◽

Small Cell Lung ◽

Sea Hare ◽

Cell Death Pathways ◽

Anticancer Effects ◽

Regulated Cell Death

Sea hare-derived compounds induce macrophage activation and reduce asthmatic parameters in mouse models of allergic asthma. These findings led us to study the role of sea hare hydrolysates (SHH) in cancer pathophysiology. SHH treatment-induced M1 macrophage activation in RAW264.7 cells, peritoneal macrophages, and THP-1 cells, as did lipopolysaccharide (LPS) (+ INF-γ), whereas SHH reduced interleukin (IL)-4 (+IL-13)-induced M2 macrophage polarization. In addition, SHH treatment inhibited the actions of M1 and M2 macrophages, which have anticancer and pro-cancer effects, respectively, in non-small cell lung cancer cells (A549 and HCC-366) and tumor-associated macrophages (TAMs). Furthermore, SHH induced G2/M phase arrest and cell death in A549 cells. SHH also downregulated STAT3 activation in macrophages and A549 cells, and the down-regulation was recovered by colivelin, a STAT3 activator. SHH-induced reduction of M2 polarization and tumor growth was blocked by colivelin treatment. SHH-induced cell death did not occur in the manner of apoptotic signaling pathways, while the death pattern was mediated through pyroptosis/necroptosis, which causes membrane rupture, formation of vacuoles and bleb, activation of caspase-1, and secretion of IL-1β in SHH-treated A549 cells. However, a combination of SHH and colivelin blocked caspase-1 activation. Z-YVAD-FMK and necrostatin-1, pyrotosis and necroptosis inhibitors, attenuated SHH’s effect on the cell viability of A549 cells. Taken together, SHH showed anticancer effects through a cytotoxic effect on A549 cells and a regulatory effect on macrophages in A549 cells. In addition, the SHH-induced anticancer effects were mediated by non-apoptotic regulated cell death pathways under STAT3 inhibition. These results suggest that SHH may be offered as a potential remedy for cancer immunotherapy.

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Chrysophanol-induced cell death (necrosis) in human lung cancer A549 cells is mediated through increasing reactive oxygen species and decreasing the level of mitochondrial membrane potential

Environmental Toxicology ◽

10.1002/tox.21801 ◽

2012 ◽

Vol 29 (7) ◽

pp. 740-749 ◽

Cited By ~ 35

Author(s):

Chien-Hang Ni ◽

Chun-Shu Yu ◽

Hsu-Feng Lu ◽

Jai-Sing Yang ◽

Hui-Ying Huang ◽

...

Keyword(s):

Lung Cancer ◽

Reactive Oxygen Species ◽

Cell Death ◽

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Human Lung ◽

A549 Cells ◽

Human Lung Cancer ◽

Oxygen Species

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Down-Regulation of Claudin-2 Expression by Cyanidin-3-Glucoside Enhances Sensitivity to Anticancer Drugs in the Spheroid of Human Lung Adenocarcinoma A549 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22020499 ◽

2021 ◽

Vol 22 (2) ◽

pp. 499

Author(s):

Hiroaki Eguchi ◽

Haruka Matsunaga ◽

Saki Onuma ◽

Yuta Yoshino ◽

Toshiyuki Matsunaga ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Human Lung ◽

A549 Cells ◽

Integral Membrane Protein ◽

Hydroxyl Group ◽

Transcriptional Level ◽

Hydroxyl Groups ◽

P38 Inhibitor ◽

Human Lung Adenocarcinoma ◽

Lung Adenocarcinoma A549

Claudin-2 (CLDN2), an integral membrane protein located at tight junctions, is abnormally expressed in human lung adenocarcinoma tissues, and is linked to drug resistance in human lung adenocarcinoma A549 cells. CLDN2 may be a target for the prevention of lung adenocarcinoma, but there are few compounds which can reduce CLDN2 expression. We found that cyanidin-3-glucoside (C3G), the anthocyanin with two hydroxyl groups on the B-ring, and cyanidin significantly reduce the protein level of CLDN2 in A549 cells. In contrast, pelargonidin-3-glucoside (P3G), the anthocyanin with one hydroxyl group on the B-ring, had no effect. These results suggest that cyanidin and the hydroxyl group at the 3-position on the B-ring play an important role in the reduction of CLDN2 expression. The phosphorylation of Akt, an activator of CLDN2 expression at the transcriptional level, was inhibited by C3G, but not by P3G. The endocytosis and lysosomal degradation are suggested to be involved in the C3G-induced decrease in CLDN2 protein expression. C3G increased the phosphorylation of p38 and the p38 inhibitor SB203580 rescued the C3G-induced decrease in CLDN2 expression. In addition, SB203580 rescued the protein stability of CLDN2. C3G may reduce CLDN2 expression at the transcriptional and post-translational steps mediated by inhibiting Akt and activating p38, respectively. C3G enhanced the accumulation and cytotoxicity of doxorubicin (DXR) in the spheroid models. The percentages of apoptotic and necrotic cells induced by DXR were increased by C3G. Our data suggest that C3G-rich foods can prevent the chemoresistance of lung adenocarcinoma A549 cells through the reduction of CLDN2 expression.

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Activation of ERK–p53 and ERK-Mediated Phosphorylation of Bcl-2 Are Involved in Autophagic Cell Death Induced by the c-Met Inhibitor SU11274 in Human Lung Cancer A549 Cells

Journal of Pharmacological Sciences ◽

10.1254/jphs.11181fp ◽

2012 ◽

Vol 118 (4) ◽

pp. 423-432 ◽

Cited By ~ 50

Author(s):

Ying Liu ◽

Ying Yang ◽

Yuan-Chao Ye ◽

Qi-Feng Shi ◽

Kuan Chai ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Human Lung ◽

A549 Cells ◽

Autophagic Cell Death ◽

Human Lung Cancer ◽

Met Inhibitor

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Antiproliferative and Apoptotic Effects ofSesbania grandifloraLeaves in Human Cancer Cells

BioMed Research International ◽

10.1155/2014/474953 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 36

Author(s):

Sankar Pajaniradje ◽

Kumaravel Mohankumar ◽

Ramya Pamidimukkala ◽

Srividya Subramanian ◽

Rukkumani Rajagopalan

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Medicinal Plant ◽

Cancer Cell ◽

Human Cancer ◽

A549 Cells ◽

Cancer Cell Line ◽

Lung Cancer Cell Line ◽

Human Lung Cancer ◽

Dapi Staining

Natural phytochemicals and their derivatives are good drug candidates for anticancer therapeutic approaches against multiple targets. We report here the initial findings from our studies on the anticancer properties of the leaves of the medicinal plantSesbania grandiflora. In the current study, five different solvent fractions from the leaves ofS. grandiflorawere tested on cancer cell lines such as MCF-7, HepG2, Hep-2, HCT-15, and A549. The methanolic fraction ofS. grandiflorawas found to exert potent antiproliferative effects especially in the human lung cancer cell line, A549. Caspase 3 was activated in the methanolic fraction treated A549 cells thereby leading to cell death by apoptosis. DAPI staining, DNA laddering, and decrease in mitochondrial membrane potential further confirmed the apoptotic mode of cell death. The high levels of ROS intermediates as evidenced by DCF-DA staining could have played a role in the apoptotic induction. Decrease in levels of cyclin D1 and decrease in the activation of NFkB were observed in A549 cells on treatment with methanolic fraction, giving a hint on the possible mechanism of action. These results prove that the medicinal plantS. grandifloracan be explored further for promising candidate molecules to combat cancer, especially lung cancer.

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Artemisia santolinifolia-Mediated Chemosensitization via Activation of Distinct Cell Death Modes and Suppression of STAT3/Survivin-Signaling Pathways in NSCLC

Molecules ◽

10.3390/molecules26237200 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7200

Author(s):

Uyanga Batbold ◽

Jun-Jen Liu

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cell Lines ◽

Therapeutic Option ◽

A549 Cells ◽

Annexin V ◽

Ethanol Extract ◽

Conventional Chemotherapy ◽

Cell Death Pathways ◽

Distinct Cell

Conventional chemotherapy remains an integral part of lung cancer therapy, regardless of its toxicity and drug resistance. Consequently, the discovery of an alternative to conventional chemotherapy is critical. Artemisia santolinifolia ethanol extract (AS) was assessed for its chemosensitizer ability when combined with the conventional anticancer drug, docetaxel (DTX), against non-small cell lung cancer (NSCLC). SRB assay was used to determine cell viability for A549 and H23 cell lines. The potential for this combination was examined by the combination index (CI). Further cell death, analyses with Annexin V/7AAD double staining, and corresponding protein expressions were analyzed. Surprisingly, AS synergistically enhanced the cytotoxic effect of DTX by inducing apoptosis in H23 cells through the caspase-dependent pathway, whereas selectively increased necrotic cell population in A549 cells, following the decline in GPX4 level and reactive oxygen species (ROS) activation with the highest rate in the combination treatment group. Furthermore, our results highlight the chemosensitization ability of AS when combined with DTX. It was closely associated with synergistic inhibition of oncogenesis signaling molecule STAT3 in both cell lines and concurrently downregulating prosurvival protein Survivin. Conclusively, AS could enhance DTX-induced cancer cells apoptosis by abrogating substantial prosurvival proteins’ expressions and triggering two distinct cell death pathways. Our data also highlight that AS might serve as an adjunctive therapeutic option along with a conventional chemotherapeutic agent in the management of NSCLC patients.

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