Honokiol Induces Apoptosis, G1 Arrest, and Autophagy in KRAS Mutant Lung Cancer Cells

Luo, Lianxiang; Liu, Ying; Liu, Zhongqiu; Fan, Xing‐Xing; Duan, Fang; Li, Runze; Yao, Xiaojun; Leung, Elaine Lai‐Han; Liu, Liang

doi:10.3389/fphar.2017.00199

Cited by 51 publications

(30 citation statements)

References 54 publications

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“…Apoptosis, autophagy and pyroptosis are three main types of cell death [40]. Many traditional chemotherapies for NSCLC, such as gefitinib, cisplatin, paclitaxel, erlotinib and crizotinib, were reported to induce cell apoptotic and autophagic death to inhibit tumor growth and cell proliferation [41][42][43][44]. However, there are limited studies on the involvement of pyroptosis and related drugs for NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

Teng

Mei

Zhou

et al. 2020

Cancers

231

146

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Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen Cancers 2020, 12, 193 2 of 27 species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.

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Section: Discussionmentioning

confidence: 99%

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

Teng

Mei

Zhou

et al. 2020

Cancers

231

146

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“…In these researches, HNK owned a wealth of approaches by which it buffers inflammatory and oxidative damage, such as JAK/STAT, sirtuins, Stat3/Zeb1/E‐cadherin axis, amyloidogenic pathway, and mitochondrial dynamics . Meanwhile, HNK can activate the expression of SIRT3 and sirtuins, which confer protection against many pathological conditions including ischemic injury, cancer, and aging . Thereby, the relationships among cognitive deficit, neuroinflammation, oxidative stress, and SIRT3 expression in adult mice subjected to surgery/anesthesia were focused in recently.…”

Section: Discussionmentioning

confidence: 99%

“…[31][32][33][34][35] Meanwhile, HNK can activate the expression of SIRT3 and sirtuins, which confer protection against many pathological conditions including ischemic injury, cancer, and aging. 36,37 Thereby, the relationships among cognitive deficit, neuroinflammation, oxidative stress, and SIRT3 expression in adult mice subjected to surgery/anesthesia were focused in recently. delirium.…”

Section: Effects Of Honokiol On Sirt3/sod2 Signaling Pathwaymentioning

confidence: 99%

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

Chen

et al. 2018

CNS Neurosci Ther

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Aims Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia‐induced cognitive decline in mice. Methods Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia and HNK or SIRT3 inhibitor (3‐TYP) treatment. Cognitive function and locomotor activity of mice were evaluated using fear conditioning test and open field test on postoperative 1 and 3 days. Neuronal apoptosis in CA1 and CA3 area of hippocampus was examined using TUNEL assay. And Western blot was applied to measure the expression of pro‐inflammatory cytokines and SIRT3/SOD2 signaling‐associated proteins in hippocampus. Meanwhile, SIRT3 positive cells were calculated by immunohistochemistry. The mitochondrial membrane potential, malondialdehyde (MDA), and mitochondrial radical oxygen species (mtROS) were detected using standard methods. Results Honokiol attenuated surgery‐induced memory loss and neuronal apoptosis, decreased neuroinflammatory response, and ameliorated oxidative damage in hippocampus. Notably, surgery/anesthesia induced an obviously decrease in hippocampal SIRT3 expression, whereas the HNK increased SIRT3 expression and thus decreased the acetylation of superoxide dismutase 2 (SOD2). However, 3‐TYP treatment inhibited the HNK's rescuing effects. Conclusions These results suggested that activation of SIRT3 by honokiol may attenuate surgery/anesthesia‐induced cognitive impairment in mice through regulation of oxidative stress and neuroinflammatory in hippocampus.

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“…In KRAS mutant lung cancer cells, it was discovered that Sirt3 was significantly up-regulated in honokiol-treated KRAS mutant lung cancer cells, leading to the destabilisation of its target gene Hif-1α and induction of G1 arrest and apoptosis. This suggests that the anticancer property of honokiol is regulated via a novel mechanism associated with the Sirt3/Hif-1α [49].…”

Section: Hypoxia-inducible-factor (Hif) Pathwaymentioning

confidence: 97%

Honokiol: A Review of Its Anticancer Potential and Mechanisms

Ong

Lee

Tang

et al. 2019

Cancers

122

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Cancer is characterised by uncontrolled cell division and abnormal cell growth, which is largely caused by a variety of gene mutations. There are continuous efforts being made to develop effective cancer treatments as resistance to current anticancer drugs has been on the rise. Natural products represent a promising source in the search for anticancer treatments as they possess unique chemical structures and combinations of compounds that may be effective against cancer with a minimal toxicity profile or few side effects compared to standard anticancer therapy. Extensive research on natural products has shown that bioactive natural compounds target multiple cellular processes and pathways involved in cancer progression. In this review, we discuss honokiol, a plant bioactive compound that originates mainly from the Magnolia species. Various studies have proven that honokiol exerts broad-range anticancer activity in vitro and in vivo by regulating numerous signalling pathways. These include induction of G0/G1 and G2/M cell cycle arrest (via the regulation of cyclin-dependent kinase (CDK) and cyclin proteins), epithelial-mesenchymal transition inhibition via the downregulation of mesenchymal markers and upregulation of epithelial markers. Additionally, honokiol possesses the capability to supress cell migration and invasion via the downregulation of several matrix-metalloproteinases (activation of 5 AMP-activated protein kinase (AMPK) and KISS1/KISS1R signalling), inhibiting cell migration, invasion, and metastasis, as well as inducing anti-angiogenesis activity (via the down-regulation of vascular endothelial growth factor (VEGFR) and vascular endothelial growth factor (VEGF)). Combining these studies provides significant insights for the potential of honokiol to be a promising candidate natural compound for chemoprevention and treatment.

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Honokiol Induces Apoptosis, G1 Arrest, and Autophagy in KRAS Mutant Lung Cancer Cells

Cited by 51 publications

References 54 publications

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

Honokiol: A Review of Its Anticancer Potential and Mechanisms

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