Honokiol, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells

Lu, Chieh-Hsiang; Chen, Shu-Hsin; Chang, Yu-Chieh; Liu, Yiwen; Wu, Jin‐Yi; Lim, Yun-Ping; Yu, Hui-I; Lee, Ying‐Ray

doi:10.1016/j.phrs.2016.11.038

Cited by 51 publications

(40 citation statements)

References 39 publications

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“…In our study, in KRAS mutant cells, honokiol caused the conversion of LC3-I to LC3-II, which provided an indicator of autophagic activity and could be reversed by autophagy inhibitor 3-MA, displaying its ability of inducing autophagy. Furthermore, our results revealed that honokiol-induced autophagy is dependent on the AMPK-mTOR signaling pathway, which has been addressed in autophagocytosis (Lin et al, 2016; Lu et al, 2017). Honokiol-induced autophagy may perform a pro-death process in KRAS mutant lung cancer cells, but not pro-survival response, as autophagy inhibitor 3-MA was application reduced honokiol-mediated cytotoxicity.…”

Section: Discussionmentioning

confidence: 62%

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

Luo

Liu

et al. 2017

Front. Pharmacol.

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Aberrant signaling transduction induced by mutant KRAS proteins occurs in 20∼30% of non-small cell lung cancer (NSCLC), however, a direct and effective pharmacological inhibitor targeting KRAS has not yet reached the clinic to date. Honokiol, a small molecular polyphenol natural biophenolic compound derived from the bark of magnolia trees, exerts anticancer activity, however, its mechanism remains unknown. In this study, we sought to investigate the in vitro effects of honokiol on NSCLC cell lines harboring KRAS mutations. Honokiol was shown to induce G1 arrest and apoptosis to inhibit the growth of KRAS mutant lung cancer cells, which was weakened by an autophagy inhibitor 3-methyladenine (3-MA), suggesting a pro-apoptotic role of honokiol-induced autophagy that was dependent on AMPK-mTOR signaling pathway. In addition, we also discovered that Sirt3 was significantly up-regulated in honokiol treated KRAS mutant lung cancer cells, leading to destabilization of its target gene Hif-1α, which indicated that the anticancer property of honokiol maybe regulated via a novel mechanism associated with the Sirt3/Hif-1α. Taken together, these results broaden our understanding of the mechanisms on honokiol effects in lung cancer, and reinforce the possibility of its potential anticancer benefit as a popular Chinese herbal medicine (CHM).

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Section: Discussionmentioning

confidence: 62%

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

Luo

Liu

et al. 2017

Front. Pharmacol.

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“…In addition, it has been reported that honokiol inhibits anti-apoptotic gene products including cIAP1/2, Bcl-2, c-FLIP and survivin through the down-regulation of Akt-and NF-jB-related pathways [52,53]. Suppression of Akt/mTOR pathway was also reported to alter autophagy activation in human thyroid cancer cells [54]. Therefore, the results of OSCC cells treated with honokiol were in line with others, and honokiol-mediated apoptosis and/or autophagy in human OSCCs may involve the down-regulation of Akt and related anti-apoptotic or anti-autophagic factors.…”

Section: Discussionmentioning

confidence: 99%

Honokiol inhibits in vitro and in vivo growth of oral squamous cell carcinoma through induction of apoptosis, cell cycle arrest and autophagy

Huang

Kuo

Chen

et al. 2018

J Cellular Molecular Medi

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Honokiol, an active natural product derived from Magnolia officinalis, exerted anticancer effects through a variety of mechanisms on multiple types of cancers. In this study, the molecular mechanisms of honokiol in suppressing the human oral squamous cell carcinoma (OSCC) cells were evaluated. Treatment of two OSCC cell lines with honokiol resulted in reducing the cell proliferation and arresting the cell cycle at G1 stage which was correlated with the down‐regulation of Cdk2 and Cdk4 and the up‐regulation of cell cycle suppressors, p21 and p27. In addition, the caspase‐dependent programmed cell death was substantially detected, and the autophagy was induced as the autophagosome formation and autophagic flux proceeded. Modulation of autophagy by autophagic inducer, rapamycin or inhibitors, 3‐MA or bafilomycin, potentiated the honokiol‐mediated anti‐OSCC effects where honokiol exerted multiple actions in suppression of MAPK pathway and regulation of Akt/mTOR or AMPK pathways. As compared to clinical therapeutic agent, 5‐FU, honokiol exhibited more potent activity against OSCC cells and synergistically enhanced the cytotoxic effect of 5‐FU. Furthermore, orally administrated honokiol exerted effective antitumour activity in vivo in OSCC‐xenografted mice. Thus, this study revealed that honokiol could be a promising candidate in preventing human OSCCs.

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“…Other signalling pathways are also found to be involved in honokiol-induced autophagy including the involvement of AMPK-mTOR signalling pathway which leads to autophagocytosis through the coordinated phosphorylation of Ulk1 in Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant lung cancer and melanoma cells [55,60,66,97]. Besides this, the ROS/ERK1/2 signalling pathway is also believed to play a certain role in honokiol-induced autophagy though ERK activation and the generation of ROS in treated osteosarcoma cells [67,77,97].…”

Section: Autophagymentioning

confidence: 99%

“…However, the actual mechanism of autophagy in cancer remains unclear. Several studies have highlighted the potential of honokiol to induce cell death via autophagy in human prostate cancer cells [77], human glioma cells [138], NSCLC cells [30], and human thyroid cancer cells [60].…”

Section: Autophagymentioning

confidence: 99%

Honokiol: A Review of Its Anticancer Potential and Mechanisms

Ong

Lee

Tang

et al. 2019

Cancers

131

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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, a potential therapeutic agent, induces cell cycle arrest and program cell death in vitro and in vivo in human thyroid cancer cells

Cited by 51 publications

References 39 publications

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

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

Honokiol inhibits in vitro and in vivo growth of oral squamous cell carcinoma through induction of apoptosis, cell cycle arrest and autophagy

Honokiol: A Review of Its Anticancer Potential and Mechanisms

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