Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways

Yang, Jianhong; Pei, Heying; Luo, Hong; Fu, Afu; Yang, Hansuo; Hu, Jia; Zhao, Chengjian; Chai, LuLu; Chen, Xiang; Shao, Ximing; Wang, Qianqian; Wu, Wenshuang; Wan, Li; Ye, Haoyu; Qiu, Qiang; Peng, Aihua; Wei, Yuquan; Yang, Li; Chen, Lijuan

doi:10.18632/oncotarget.13687

Cited by 24 publications

(19 citation statements)

References 44 publications

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“…MYC amplification co-occurring with EGFR activation was frequently observed in advanced HCC [ 27 ]. In addition, the crucial proteins of the PTGS2 signaling pathway such as AKT, STK33, and MTOR were all elevated in COX-2-driven HCC; thus, targeting these proteins could active these oncogenic cascades by COX-2 overexpression during the pathogenesis of HCC [ 30 ]. More importantly, these pathways and genes might cooperate in promoting metastasis of HCC through crosstalk between cancer and immune microenvironment [ 27 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objective. To investigate the potential active ingredients and underlying mechanisms of Artemisia annua (AA) on the treatment of hepatocellular carcinoma (HCC) based on network pharmacology. Methods. In the present study, we used a network pharmacological method to predict its underlying complex mechanism of treating HCC. First, we obtained relative compounds of AA based on the traditional Chinese medicine systems pharmacology (TCMSP) database and collected potential targets of these compounds by target fishing. Then, we built HCC-related targets target by the oncogenomic database of hepatocellular carcinoma (OncoDB.HCC) and biopharmacological network (PharmDB-K) database. Based on the matching results between AA potential targets and HCC targets, we built a protein-protein interaction (PPI) network to analyze the interactions among these targets and screen the hub targets by topology. Furthermore, the function annotation and signaling pathways of key targets were performed by Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using DAVID tools. Finally, the binding capacity between active ingredients and key targets was validated by molecular docking. Results. A total of 19 main active ingredients of AA were screened as target prediction; then, 25 HCC-related common targets were seeked out via multiple HCC databases. The areas of nodes and corresponding degree values of EGFR, ESR1, CCND1, MYC, EGF, and PTGS2 were larger and could be easily found in the PPI network. Furthermore, GO and KEGG enrichment analysis showed that these key targets were significantly involved in multiple biological processes and pathways which participated in tumor cell proliferation, apoptosis, angiogenesis, tumor invasion, and metastasis to accomplish the anti-HCC activity. The molecular docking analysis showed that quercetin could stably bind to the active pocket of EGFR protein 4RJ5 via LibDock. Conclusion. The anticancer effects of AA on HCC were predicted to be associated with regulating tumor cell proliferation, apoptosis, angiogenesis, tumor invasion, and metastasis via various pathways such as the EGFR signaling pathway, ESR1 signaling pathway, and CCND1 signaling pathway. It is suggested that AA might be developed as a broad-spectrum antitumor drug based on its characteristics of multicomponent, multipath, and multitarget.

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Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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“…The promotion of cancer metastasis by MMP‐9 through EGFR‐mediated signaling pathway has been addressed (Cowden Dahl et al, ; Yang et al, ). The suppression of cancer cell metastasis thru the down‐regulation of EGFR‐activated MMP‐9 has been presented (Chung et al, ; Lin et al, ; Tse et al, ; Yang et al, ). Honokiol has been verified to inhibit the EGFR‐mediated signaling pathway through activity suppression and protein degradation (Liou et al, ; Yang et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The suppression of cancer cell metastasis thru the down‐regulation of EGFR‐activated MMP‐9 has been presented (Chung et al, ; Lin et al, ; Tse et al, ; Yang et al, ). Honokiol has been verified to inhibit the EGFR‐mediated signaling pathway through activity suppression and protein degradation (Liou et al, ; Yang et al, ). Accordingly, honokiol‐down‐regulated MMP‐9 expression might be possible through the repression of EGFR‐mediated signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, honokiol‐down‐regulated MMP‐9 expression might be possible through the repression of EGFR‐mediated signaling pathway. Nevertheless, EGFR‐activated MMP‐9 expression is through transcriptional factor‐drove MMP‐9 gene expression, such as NF‐κB or Sp‐1, but not the regulation of post‐translational mechanism (Lin et al, ; Yang et al, ). Hence, down‐regulated MMP‐9 expression thru the suppression of EGFR‐mediated signaling by honokiol was excluded in our system.…”

Section: Discussionmentioning

confidence: 99%

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Suppressing migration and invasion of H1299 lung cancer cells by honokiol through disrupting expression of an HDAC6‐mediated matrix metalloproteinase 9

Pai

Hsu

Hsieh

et al. 2020

Food Science & Nutrition

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Metastasis is the crucial mechanism to cause high mortality in lung cancer. Degradation of extracellular matrix (ECM) by proteolytic enzymes, especially matrix metalloproteinases (MMPs), is a key process for promoting cancer cell migration and invasion. Therefore, targeting MMPs might be a strategy for lung cancer metastasis suppression. Honokiol, a biological active component of Magnolia officinalis, has been indicated to suppress lung cancer tumorigenesis through epigenetic regulation. However, the regulation of MMPs‐mediated migration and invasion by honokiol through epigenetic regulation in lung cancer is still a mystery. In the present study, the migration and invasion ability of H1299 lung cancer was suppressed by noncytotoxic concentrations of honokiol treatment. The proteolytic activity of MMP‐9, rather than MMP‐2, was inhibited in honokiol‐treated H1299 cells. Honokiol‐inhibited MMP‐9 expression was through promoting MMP‐9 protein degradation rather than suppressing transcription mechanism. Furthermore, the expression of specific histone deacetylases 6 (HDAC6) substrate, acetyl‐α‐tubulin, was accumulated after honokiol incubation. The disassociation of MMP‐9 with hyper‐acetylated heat shock protein 90 (Hsp90) was observed resulting in MMP‐9 degradation after honokiol treatment. Meanwhile, honokiol‐suppressed MMP‐9 expression and invasion ability of H1299 lung cancer cells was rescued by HDAC6 overexpression. Accordingly, the results suggested that the suppression of migration and invasion activities by honokiol was through inhibiting HDAC6‐mediated Hsp90/MMP‐9 interaction and followed by MMP‐9 degradation in lung cancer.

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“…However, the poor aqueous solubility of magnolol 1 and honokiol 2 , and in general, of naturally-occurring polyphenols, has hampered the clinical applications of this kind of compounds, which possess a wide variety of biological activities. In order to overcome this issue, encapsulation of honokiol have been assessed [ 39 , 40 ] and synthetic derivatives have been prepared [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of magnolol and honokiol derivatives and their effect against hepatocarcinoma cells

et al. 2018

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The hepatocellular carcinoma is one of the most common malignant tumour with high level of mortality rate due to its rapid progression and high resistance to conventional chemotherapies. Thus, the search for novel therapeutic leads is of global interest. Herein, a small set of derivatives of magnolol 1 and honokiol 2, the main components of Magnolia grandiflora and Magnolia obovata, were evaluated in in vitro assay using tumoral hepatocytes. The pro-drug approach was applied as versatile strategy to the improve bioactivity of the compounds by careful transformation of the hydroxyl groups of magnolol 1 and honokiol 2 in suitable ester derivatives. Compounds 10 and 11 resulted to be more potent than the parental honokiol 2 at concentration down to 1 μM with complete viability of treated fibroblast cells up to concentrations of 80 μM. The combination of a butyrate ester and a bare phenol-OH group in the honokiol structure seemed to play a significant role in the antiproliferative activity identifying an interesting pharmacological clue against hepatocellular carcinoma.

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Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways

Cited by 24 publications

References 44 publications

A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma

A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma

Suppressing migration and invasion of H1299 lung cancer cells by honokiol through disrupting expression of an HDAC6‐mediated matrix metalloproteinase 9

Synthesis of magnolol and honokiol derivatives and their effect against hepatocarcinoma cells

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