Honokiol Articles 5

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Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.
            (Averett et al., 2016) Download
The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo . We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factor-kappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.

Modified citrus pectin anti-metastatic properties: one bullet, multiple targets.
            (Glinsky and Raz, 2009) Download
In this minireview, we examine the ability of modified citrus pectin (MCP), a complex water soluble indigestible polysaccharide obtained from the peel and pulp of citrus fruits and modified by means of high pH and temperature treatment, to affect numerous rate-limiting steps in cancer metastasis. The anti-adhesive properties of MCP as well as its potential for increasing apoptotic responses of tumor cells to chemotherapy by inhibiting galectin-3 anti-apoptotic function are discussed in the light of a potential use of this carbohydrate-based substance in the treatment of multiple human malignancies.

Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC).
            (Godugu et al., 2017) Download
Triple negative breast cancer (TNBC), owing to its aggressive behavior and toxicity associated with available chemotherapy; currently no suitable therapy is available. Honokiol (HNK) is a promising anticancer drug but has poor bioavailability. In the current study, we evaluated the anticancer effects of an oral Honokiol nanomicellar (NM) formulation (size range of 20-40nm) in vitro against various TNBC cells lines. Cytotoxicity, clonogenic and wound healing assays demonstrated the promising anticancer effects. In vitro Caco-2 permeability studies suggested increased absorption of Honokiol. Compared to HNK-FD, nanomicellar formulations resulted in significant increase in the oral bioavailability. C

Antineoplastic Effects of Honokiol on Melanoma.
            (Guillermo-Lagae et al., 2017)  Download
Honokiol, a plant lignan has been shown to have antineoplastic effects against nonmelanoma skin cancer developments in mice. In this study, antineoplastic effects of honokiol were investigated in malignant melanoma models. In vitro effects of honokiol treatment on SKMEL-2 and UACC-62 melanoma cells were evaluated by measuring the cell viability, proliferation, apoptosis, cell cycle analysis, and expressions of various proteins associated with cell cycle progression and apoptosis. For the in vivo study, male nude mice inoculated with SKMEL-2 or UACC-62 cells received injections of sesame oil or honokiol for two to seven weeks. In vitro honokiol treatment caused significant decrease in cell viability, proliferation, cell cycle arrest, increased apoptosis, and modulation of apoptotic and cell cycle regulatory proteins. Honokiol caused an accumulation of cells in the G2/M phase of the cell cycle in SKMEL-2 and G0/G1 phase in UACC-62 cells. An elevated level of caspases and PARP were observed in both cell lines treated with honokiol. A decrease in the expression of various cell cycle regulatory proteins was also observed in honokiol treated cells. Honokiol caused a significant reduction of tumor growth in SKMEL-2 and UACC-62 melanoma xenografts. These findings suggest that honokiol is a good candidate for further studies as a possible treatment for malignant melanoma.


 

Anti-inflammatory Nutraceuticals and Chronic Diseases (BOOK)
(Gupta et al., 2016) Download

Honokiol induces cell cycle arrest and apoptosis via inhibition of survival signals in adult T-cell leukemia.
            (Ishikawa et al., 2012) Download
BACKGROUND:  Honokiol, a naturally occurring biphenyl, possesses anti-neoplastic properties. We investigated activities of honokiol against adult T-cell leukemia (ATL) associated with human T-cell leukemia virus type 1 (HTLV-1). METHODS:  Cell viability was assessed using colorimetric assay. Propidium iodide staining was performed to determine cell cycle phase. Apoptotic effects were evaluated by 7A6 detection and caspases activity. Expressions of cell cycle- and apoptosis-associated proteins were analyzed by Western blot. We investigated the efficacy of honokiol in mice harboring tumors of HTLV-1-infected T-cell origin. RESULTS:  Honokiol exhibited cytotoxic activity against HTLV-1-infected T-cell lines and ATL cells. We identified two different effects of honokiol on HTLV-1-infected T-cell lines: cell cycle inhibition and induction of apoptosis. Honokiol induced G1 cell cycle arrest by reducing the expression of cyclins D1, D2, E, CDK2, CDK4, CDK6 and c-Myc, while apoptosis was induced via reduced expression of cIAP-2, XIAP and survivin. The induced apoptosis was also associated with activation of caspases-3 and -9. In addition, honokiol suppressed the phosphorylation of IκBα, IKKα, IKKβ, STAT3, STAT5 and Akt, down-regulated JunB and JunD, and inhibited DNA binding of NF-κB, AP-1, STAT3 and STAT5. These effects resulted in the inactivation of survival signals including NF-κB, AP-1, STATs and Akt. Honokiol was highly effective against ATL in mice CONCLUSIONS:  Our data suggested that honokiol is a systemically available, non-toxic inhibitor of ATL cell growth that should be examined for potential clinical application. GENERAL SIGNIFICANCE:  Our findings provide a rationale for clinical evaluation of honokiol for the management of ATL.

Multiple effects of Honokiol on the life cycle of hepatitis C virus.
            (Lan et al., 2012) Download
BACKGROUND:  Honokiol, a small active molecular compound extracted from magnolia, has recently been shown to inhibit hepatitis C virus (HCV) infection in vitro. AIMS:  This study further characterized aspects of the HCV lifecycle affected by the antiviral functions of honokiol. METHODS:  The influence of honokiol on HCV infection, entry, translation and replication was assessed in Huh-7.5.1 cells using cell culture-derived HCV (HCVcc), HCV pseudo-type (HCVpp) and sub-genomic replicons. RESULTS:  Honokiol had strong antiviral effect against HCVcc infection at non-toxic concentrations. Combined with interferon-α, its inhibitory effect on HCVcc was more profound than that of ribavirin. Honokiol inhibited the cell entry of lentiviral particles pseudo-typed with glycoproteins from HCV genotypes 1a, 1b, and 2a, but not of the vesicular stomatitis virus. It had inefficient activity on HCV internal ribosome entry site (IRES)-translation at concentrations with significant anti-HCVcc effects. The expression levels of components of replication complex, NS3, NS5A and NS5B, were down-regulated by honokiol in a dose-dependent manner. It also inhibited HCV replication dose dependently in both genotypes 1b and 2a sub-genomic replicons. CONCLUSIONS:  Honokiol inhibits HCV infection by targeting cell entry and replication and, only at a concentration >30 μM, IRES-mediated translation of HCV life cycle. Based on its high therapeutic index (LD(50) /EC(90)  = 5.4), honokiol may be a promising drug for the treatment of HCV infection.

Honokiol, an Active Compound of Magnolia Plant, Inhibits Growth, and Progression of Cancers of Different Organs.
            (Prasad and Katiyar, 2016) Download
Honokiol (C18H18O2) is a biphenolic natural product isolated from the bark and leaves of Magnolia plant spp. During the last decade or more, honokiol has been extensively studied for its beneficial effect against several diseases. Investigations have demonstrated that honokiol possesses anti-carcinogenic, anti-inflammatory, anti-oxidative, anti-angiogenic as well as inhibitory effect on malignant transformation of papillomas to carcinomas in vitro and in vivo animal models without any appreciable toxicity. Honokiol affects multiple signaling pathways, molecular and cellular targets including nuclear factor-jB (NF-jB), STAT3, epidermal growth factor receptor (EGFR), cell survival signaling, cell cycle, cyclooxygenase and other inflammatory mediators, etc. Its chemopreventive and/or therapeutic effects have been tested against chronic diseases, such as cancers of different organs. In this chapter, we describe and discuss briefly the effect of honokiol against cancers of different organs, such as melanoma, non-melanoma, lung, prostate, breast, head and neck squamous cell carcinoma, urinary bladder cancer, gastric cancer, and neuroblastoma, etc. and describe its mechanism of action including various molecular and cellular targets. Although more rigorous in vivo studies are still needed, however it is expected that therapeutic effects and activities of honokiol may help in the development and designing of clinical trials against chronic diseases in human subjects.


 

Synergistic Antioxidant and Anti-Inflammatory Effects between Modified Citrus Pectin and Honokiol.
            (Ramachandran et al., 2017) Download
Inflammation is a normal physiological process; however, dysregulation of this process may contribute to inflammatory-based chronic disorders and diseases in animals and humans. Therefore, the antioxidant and anti-inflammatory properties of natural products, often recognized in traditional medicine systems, represent therapeutic modalities to reduce or prevent uncontrolled inflammatory processes which in turn potentially ameliorate or prevent sequelae of inflammatory-based symptoms of chronic diseases. We have investigated the antioxidant and anti-inflammatory effects of honokiol (HNK) and modified citrus pectin (MCP)

Is there a potential of misuse for Magnolia officinalis compounds/metabolites
            (Schifano et al., 2017) Download
OBJECTIVE:  Magnolia bark contains magnolol, metabolized to tetrahydromagnolol and honokiol, with both GABA-ergic/cannabimimetic activities, hence of possible attraction to vulnerable individuals/recreational misusers. METHODS:  A literature review, assessment of related anecdotal online Magnolia misuse's reports and an overview of Magnolia products' online acquisition possibilities has been here described. RESULTS:  No peer-reviewed papers about Magnolia abuse/misuse/dependence/addiction were identified. Conversely, from a range of websites emerged potentially 3 groups of Magnolia misusers: (a) subjects with a psychiatric history already treated with benzodiazepines, being attracted to Magnolia bark as a "natural sedative"; (b) polydrug misusers, ingesting Magnolia with a range of other herbs/plants, attracted by the GABA-ergic/cannabimimetic activities; (c) subjects naive to the misusing drugs' scenario, perceiving Magnolia as a natural dietary supplement/weight-control compound. CONCLUSIONS:  To the best of our knowledge, this is the first paper commenting on the possible Magnolia derivatives' potential of misuse. Magnolia's recent increase in popularity, mainly as a sedative, may be arguably due to its peculiar pharmacological properties/acceptable affordability levels/virtually worldwide favorable legal status and customers' attraction to a product being perceived as "natural" and hence somehow "safe." Future/potent/synthetic magnolol and honokiol structural analogues could however contribute to increasing the number of synthetic GABA-ergic/cannabimimetic misusing compounds.


 

Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo.
            (Singh et al., 2013) Download
Non-small-cell lung cancer (NSCLC) represents approximately 80% of all types of lung cancer. Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia grandiflora, on NSCLC cells and the molecular mechanisms underlying these effects using in vitro and in vivo models. Treatment of NSCLC cells (A549, H1299, H460 and H226) with honokiol (20, 40 and 60 µM) inhibited histone deacetylase (HDAC) activity, reduced the levels of class I HDAC proteins and enhanced histone acetyltransferase activity in a dose-dependent manner. These effects of honokiol were associated with a significant reduction in the viability of NSCLC cells. Concomitant treatment of cells with a proteasome inhibitor, MG132, prevented honokiol-induced degradation of class I HDACs, suggesting that honokiol reduced the levels of HDACs in NSCLC cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of NSCLC cells. Treatment of A549 and H1299 cells with honokiol resulted in an increase in G 1 phase arrest, and a decrease in the levels of cyclin D1, D2 and cyclin dependent kinases. Further, administration of honokiol by oral gavage significantly inhibited the growth of subcutaneous A549 and H1299 tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death and marked inhibition of class I HDACs proteins and HDAC activity in the tumor xenograft tissues. Together, our study provides new insights into the role of class I HDACs in the chemotherapeutic effects of honokiol on lung cancer cells.

Neuroprotective effects of honokiol: from chemistry to medicine.
            (Talarek et al., 2017) Download
The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities. Honokiol can permeate the blood brain barrier and the blood-cerebrospinal fluid to increase its bioavailability in neurological tissues. Diverse studies have provided evidence on the neuroprotective effect of honokiol in the central nervous system, due to its potent antioxidant activity, and amelioration of the excitotoxicity mainly related to the blockade of glutamate receptors and reduction in neuroinflammation. In addition, recent studies suggest that honokiol can attenuate neurotoxicity exerted by abnormally aggregated Aβ in Alzheimer's disease. The present work summarizes what is currently known concerning the neuroprotective effects of honokiol and its potential molecular mechanisms of action, which make it considered as a promising agent in the treatment and management of neurodegenerative diseases. © 2017 BioFactors, 43(6):760-769, 2017.

Myocardial protective effect of honokiol: an active component in Magnolia officinalis.
            (Tsai et al., 1996) Download
Honokiol is an active component of Magnolia officinalis. It was reported to be 1000 times more potent than alpha-tocopherol in inhibiting lipid peroxidation in rat heart mitochondria. In this study, we investigated the in vivo antiarrhythmic and antiischemic effects of honokiol in coronary ligated rats. Male Sprague-Dawley rats were anesthetized with urethane. Honokiol, at dosages of 10(-7) g/kg, 10(-8) g/kg, and 10(-9) g/kg, was administered intravenously 15 min before ligation of the coronary artery. Incidence and duration of ventricular tachycardia and ventricular fibrillation during 30 min coronary ligation were significantly reduced by 10(-7) g/kg honokiol. Ventricular arrhythmia during 10 min reperfusion after the relief of coronary ligation was also reduced. In rats subjected to 4 hours coronary ligation, 10(-7) g/kg, 10(-8) g/kg, and 10(-9) g/kg honokiol significantly reduced the infarct zone. We concluded that honokiol may protect the myocardium against ischemic injury and suppress ventricular arrhythmia during ischemia and reperfusion.

Cancer Chemoprevention by Phytochemicals: Nature's Healing Touch.
            (Zubair et al., 2017) Download
Phytochemicals are an important part of traditional medicine and have been investigated in detail for possible inclusion in modern medicine as well. These compounds often serve as the backbone for the synthesis of novel therapeutic agents. For many years, phytochemicals have demonstrated encouraging activity against various human cancer models in pre-clinical assays. Here, we discuss select phytochemicals-curcumin, epigallocatechin-3-gallate (EGCG), resveratrol, plumbagin and honokiol-in the context of their reported effects on the processes of inflammation and oxidative stress, which play a key role in tumorigenesis. We also discuss the emerging evidence on modulation of tumor microenvironment by these phytochemicals which can possibly define their cancer-specific action. Finally, we provide recent updates on how low bioavailability, a major concern with phytochemicals, is being circumvented and the general efficacy being improved, by synthesis of novel chemical analogs and nanoformulations.

 


References

Averett, C, et al. (2016), ‘Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.’, Carcinogenesis, 37 (11), 1052-61. PubMed: 27609457
Glinsky, VV and A Raz (2009), ‘Modified citrus pectin anti-metastatic properties: one bullet, multiple targets.’, Carbohydr Res, 344 (14), 1788-91. PubMed: 19061992
Godugu, C, R Doddapaneni, and M Singh (2017), ‘Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC).’, Colloids Surf B Biointerfaces, 153 208-19. PubMed: 28249200
Guillermo-Lagae, R, et al. (2017), ‘Antineoplastic Effects of Honokiol on Melanoma.’, Biomed Res Int, 2017 5496398. PubMed: 28194418
Gupta, SC, S Prasad, and BB Aggarwal (2016), Anti-inflammatory Nutraceuticals and Chronic Diseases, (Springer).
Ishikawa, C, JL Arbiser, and N Mori (2012), ‘Honokiol induces cell cycle arrest and apoptosis via inhibition of survival signals in adult T-cell leukemia.’, Biochim Biophys Acta, 1820 (7), 879-87. PubMed: 22465179
Lan, KH, et al. (2012), ‘Multiple effects of Honokiol on the life cycle of hepatitis C virus.’, Liver Int, 32 (6), 989-97. PubMed: 22098176
Prasad, R and SK Katiyar (2016), ‘Honokiol, an Active Compound of Magnolia Plant, Inhibits Growth, and Progression of Cancers of Different Organs.’, Adv Exp Med Biol, 928 245-65. PubMed: 27671820
Ramachandran, C, et al. (2017), ‘Synergistic Antioxidant and Anti-Inflammatory Effects between Modified Citrus Pectin and Honokiol.’, Evid Based Complement Alternat Med, 2017 8379843. PubMed: 28900464
Schifano, F, et al. (2017), ‘Is there a potential of misuse for Magnolia officinalis compounds/metabolites’, Hum Psychopharmacol, 32 (3), PubMed: 28517911
Singh, T, R Prasad, and SK Katiyar (2013), ‘Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo.’, Epigenetics, 8 (1), 54-65. PubMed: 23221619
Talarek, S, et al. (2017), ‘Neuroprotective effects of honokiol: from chemistry to medicine.’, Biofactors, 43 (6), 760-69. PubMed: 28817221
Tsai, SK, SS Huang, and CY Hong (1996), ‘Myocardial protective effect of honokiol: an active component in Magnolia officinalis.’, Planta Med, 62 (6), 503-6. PubMed: 9000881
Zubair, H, et al. (2017), ‘Cancer Chemoprevention by Phytochemicals: Nature’s Healing Touch.’, Molecules, 22 (3), PubMed: 28273819