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| Honokiol is a Lignan isolated from bark, seed cones and leaves of trees of Magnolia species. Honokiol was traditionally used for anxiety and stroke treatment, as well as the alleviation of flu symptoms. -considered to have antioxidant properties -low oral bioavailability and difficulty in intravenous administration -the development of various formulations of honokiol, including microemulsion, liposomes, nanoparticles and micelle copolymers have successfully solved the problem of low water solubility. Pathways: -Inhibit NF-κB activation -Downregulate STAT3 signalin -Inhibiting the PI3K/Akt pathway, -Inhibition of mTOR -Influences various MAPK cascades—including ERK, JNK, and p38 -Inhibition of EGFR -Inhibiting Notch pathway (CSCs) -GPx4 inhibit -Can induce ER stress in cancer cells, which contributes to the activation of unfolded protein response (UPR) pathways -Disrupt the mitochondrial membrane potential in cancer cells. -Reported to increase ROS production in cancer cells -Can exhibit antioxidant properties in normal cells. - has some inhibitor activity but Not classified as HDAC inhibitor as weaker and may work more indirectly. - is well-known in the research community for its role in activating SIRT3 -Note half-life 40–60 minutes BioAv Pathways: - induce ROS production in cancer cells, and typically lowers ROS in normal cells - ROS↑ related: MMP↓(ΔΨm), ER Stress↑, GRP78↑, Ca+2↑">Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓ Prx - Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑, - lowers Inflammation : NF-kB↓, COX2↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, - inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, VEGF↓, ROCK1↓, RhoA↓, NF-κB↓, CXCR4↓, ERK↓ - reactivate genes thereby inhibiting cancer cell growth : HDAC↓, EZH2↓, P53↑, HSP↓, - cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓, - inhibits Migration/Invasion : TumCMig↓, TumCI↓, ERK↓, EMT↓, - inhibits glycolysis and ATP depletion : HIF-1α↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓ - inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, EGFR↓, - inhibits Cancer Stem Cells : CSC↓, CD133↓, β-catenin↓, sox2↓, nestin↓, OCT4↓, - Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK, TrxR**, - Shown to modulate the nuclear translocation of SREBP-2 (related to cholesterol). - Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective, - Selectivity: Cancer Cells vs Normal Cells Honokiol — a small, lipophilic biphenolic neolignan isolated principally from the bark, seed cones, and leaves of Magnolia species, especially Magnolia officinalis. It is a natural-product small molecule rather than a standardized Magnolia extract; the standard abbreviation is HNK. Honokiol crosses biological membranes readily and has documented CNS penetration, but its pharmaceutical development is constrained by extremely poor aqueous solubility, rapid metabolism, and low/variable oral systemic exposure. Cancer research is dominated by cell and animal studies, although an oral Phase I window-of-opportunity study in patients with resectable early-stage non-small-cell lung cancer is now enrolling. Primary mechanisms (ranked):
Bioavailability / PK relevance: Native honokiol is highly lipophilic and poorly water-soluble, limiting conventional oral and intravenous delivery. It undergoes extensive metabolic clearance, including conjugation, and systemic exposure after ordinary oral formulations may be substantially lower than concentrations commonly used experimentally. Liposomes, nanoemulsions, micelles, nanoparticles and other delivery systems can substantially improve solubility and exposure. A validated pharmacokinetic study of injectable liposomal honokiol has been reported, but clinically established human anticancer PK targets have not yet been defined. In-vitro vs systemic exposure relevance: Many anticancer studies use approximately 10–60 µM honokiol, with some models requiring still higher concentrations. These concentrations should not automatically be considered achievable following conventional oral supplementation because oral bioavailability is limited and human tumor exposure has not been established. The current Phase I lung-cancer study is therefore important for defining human tolerability, systemic exposure and pharmacodynamic effects rather than demonstrating established therapeutic efficacy. Clinical evidence status: Predominantly preclinical. Extensive in-vitro and animal anticancer evidence exists across multiple tumor types. Human anticancer efficacy has not been established. A Phase I oral honokiol study in approximately 15 patients with early-stage resectable NSCLC is currently listed by Houston Methodist as enrolling; treatment is given before surgery primarily to determine safety and maximum tolerated dose. Honokiol is not an FDA-approved anticancer drug. Safety / translation: Preclinical toxicology has generally suggested a comparatively broad therapeutic window, but concentrated honokiol should not be assumed equivalent to historical consumption of Magnolia bark preparations. Potential pharmacokinetic interactions, formulation-dependent exposure, and insufficient controlled human safety data remain major translational limitations. FDA records identify Magnolia cortex extract containing honokiol as having been submitted through the New Dietary Ingredient notification process, but this does not constitute approval of honokiol for cancer treatment. Honokiol Cancer-Relevant Mechanisms
P: 0–30 min R: 30 min–3 hr G: >3 hr Honokiol and Alzheimer’s disease: Honokiol has meaningful but entirely preclinical relevance to Alzheimer’s disease and related neurodegeneration. Its lipophilicity permits CNS penetration, and experimental studies indicate reductions in oxidative stress, neuroinflammation, excitotoxicity and Aβ-associated toxicity together with preservation of mitochondrial function. SIRT3, NRF2, PPAR/PGC-1α signaling and restoration of microglial metabolic competence are among the more plausible mechanistic axes. No convincing clinical evidence currently establishes honokiol as an AD treatment. Evidence level: Preclinical only. Cell and animal studies support neuroprotective and cognition-related effects, but human AD efficacy, dose-response relationships and long-term neurological safety have not been demonstrated. Honokiol Alzheimer’s-Relevant Mechanisms
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| In all eukaryotic cells, intracellular Ca2+ levels are maintained at low resting concentrations (approximately 100 nM) by the activity of the major Ca2+ extrusion system, the plasma membrane Ca2+-ATPase (PMCA), which exchanges extracellular protons (H+) for cytosolic Ca2+. Indeed, sustained elevation of [Ca2+]C in the form of overload, saturating all Ca2+-dependent effectors, prolonged decrease in [Ca2+]ER, causing ER stress response, and high [Ca2+]M, inducing mitochondrial permeability transition (MPT), are considered to be pro-death factors. In cancer the Ca2+-handling toolkit undergoes profound remodelling (figure 1) to favour activation of Ca2+-dependent transcription factors, such as the nuclear factor of activated T cells (NFAT), c-Myc, c-Jun, c-Fos that promote hypertrophic growth via induction of the expression of the G1 and G1/S phase transition cyclins (D and E) and associated cyclin-dependent kinases (CDK4 and CDK2). Thus, cancer cells may evade apoptosis through decreasing calcium influx into the cytoplasm. This can be achieved by either downregulation of the expression of plasma membrane Ca2+-permeable ion channels or by reducing the effectiveness of the signalling pathways that activate these channels. Such protective measures would largely diminish the possibility of Ca2+ overload in response to pro-apoptotic stimuli, thereby impairing the effectiveness of mitochondrial and cytoplasmic apoptotic pathways. Voltage-Gated Calcium Channels (VGCCs): Overexpression of VGCCs has been associated with increased tumor growth and metastasis in various cancers, including breast and prostate cancer. Store-Operated Calcium Entry (SOCE): SOCE mechanisms, such as STIM1 and ORAI1, are often upregulated in cancer cells, contributing to enhanced cell survival and proliferation. High intracellular calcium levels are associated with increased cell proliferation and migration, leading to a poorer prognosis. Calcium signaling can also influence hormone receptor status, affecting treatment responses. Increased Ca²⁺ signaling is associated with advanced disease and metastasis. Patients with higher CaSR expression may have a worse prognosis due to enhanced tumor growth and resistance to apoptosis. -Ca2+ is an important regulator of the electric charge distribution of bio-membranes. |
| 2891- | HNK, | Honokiol, an Active Compound of Magnolia Plant, Inhibits Growth, and Progression of Cancers of Different Organs |
| - | Review, | Var, | NA |
| 2863- | HNK, | Honokiol induces paraptosis-like cell death through mitochondrial ROS-dependent endoplasmic reticulum stress in hepatocellular carcinoma Hep3B cells |
| - | in-vitro, | Liver, | Hep3B |
| 2073- | HNK, | Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo |
| - | in-vitro, | OS, | U2OS | - | in-vivo, | NA, | NA |
| 2883- | HNK, | Honokiol targets mitochondria to halt cancer progression and metastasis |
| - | Review, | Var, | NA |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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