Description: <b>Glycyrrhizic acid (GA)</b> is a significant constituent of licorice root.<br>
Glycyrrhizin, the main active component obtained from licorice roots, has many pharmacological and biological functions such as protecting liver cells, anti-inflammation, anti-virus, immunomodulation, has been widely applied in the treatment of clinically related hepatic diseases (Dastagir & Rizvi, 2016). Glycyrrhizin is a natural inhibitor of HMGB1<br>
<p><b>Licorice</b> — Licorice is the dried root and stolon of <i>Glycyrrhiza</i> species, principally <i>Glycyrrhiza glabra</i>, <i>G. uralensis</i>, and <i>G. inflata</i>, used as a botanical medicine and food ingredient. It is a complex phytochemical mixture rather than a single drug. Major bioactive classes include the triterpenoid saponin glycyrrhizin (glycyrrhizic acid), its intestinal metabolite 18β-glycyrrhetinic acid, and numerous flavonoids and chalcones including liquiritigenin, isoliquiritigenin, glabridin, and species-dependent licochalcones. Standard abbreviations include LE for licorice extract and GL for glycyrrhizin. Anticancer findings are predominantly preclinical and depend strongly on species, extract preparation, constituent composition, and concentration. Glycyrrhizin is particularly important because it directly binds and inhibits extracellular HMGB1 signaling, while several flavonoid constituents contribute additional antiproliferative effects.</p>
<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>HMGB1 inhibition and suppression of HMGB1-driven inflammatory, proliferative, angiogenic, and metastatic signaling, principally attributable to glycyrrhizin.</li>
<li>Suppression of tumor proliferation and cell-cycle progression, including modulation of cyclins/CDKs and, in some models, induction of S-phase or other cell-cycle arrest.</li>
<li>Induction of cancer-cell death through mitochondrial apoptosis, caspase activation, altered BAX/BCL-2 balance, autophagy, or necrotic mechanisms depending on extract and tumor model.</li>
<li>Suppression of EMT, migration, invasion, and associated TGF-β/SMAD, cadherin, and extracellular-matrix signaling.</li>
<li>Suppression of PI3K/AKT/mTOR, STAT3, NF-κB, and related survival/inflammatory signaling in constituent- and model-dependent studies.</li>
<li>Oxidative-redox modulation (secondary): some licorice constituents increase tumor-cell ROS sufficiently to promote cell death, whereas licorice can decrease oxidative stress and activate antioxidant defenses including NRF2 in non-malignant tissues.</li>
<li>Modulation of DNA-damage responses; glycyrrhizin-HMGB1 inhibition can impair NHEJ-associated DNA repair and increase DNA damage in colorectal cancer models.</li>
<li>Anti-angiogenic signaling through reductions in VEGF/HIF-1α and related pathways in selected preclinical systems.</li>
</ol>
<p><b>Bioavailability / PK relevance:</b> Oral glycyrrhizin has low systemic exposure as intact glycyrrhizin and undergoes extensive metabolism by intestinal microbiota to glycyrrhetinic acid and additional metabolites. In a human study using a 75-mg oral glycyrrhizin dose, mean glycyrrhizin peak plasma concentration was approximately 25 ng/mL while glycyrrhetinic acid reached approximately 200 ng/mL. Consequently, systemic biology after oral licorice can differ markedly from direct exposure experiments using glycyrrhizin or crude extract. Formulation, intestinal microbiota, biliary transport, species of licorice, glycyrrhizin content, and concomitant botanicals can materially alter exposure.</p>
<p><b>In-vitro vs systemic exposure relevance:</b> Many anticancer experiments expose cells directly to licorice extracts or purified constituents at tens to hundreds of µg/mL or micromolar concentrations. These exposures frequently exceed circulating concentrations achievable after conventional oral licorice or glycyrrhizin administration. For example, recent whole-extract studies reported substantial antiproliferative effects around 30–200 µg/mL, whereas orally administered glycyrrhizin produces plasma levels in the ng/mL range and is extensively converted to metabolites. Whole-extract in-vitro anticancer potency should therefore not be interpreted as demonstrating equivalent systemic antitumor exposure in humans.</p>
<p><b>Clinical evidence status:</b> <b>Preclinical</b> for treatment or prevention of cancer. Cell and animal evidence supports several anticancer mechanisms, particularly glycyrrhizin-HMGB1 signaling and constituent-dependent antiproliferative effects. <b>Small human / RCT adjunct evidence</b> exists for supportive care rather than tumor treatment; randomized studies have reported reduced pain and severity of radiotherapy-associated oral mucositis with topical licorice preparations. There is no established clinical evidence that oral licorice treats human malignancy or improves cancer survival.</p>
<p><b>Safety / translation relevance:</b> Glycyrrhizin-containing licorice has a clinically important dose- and duration-dependent mineralocorticoid-like toxicity. Glycyrrhetinic-acid-related metabolites inhibit renal 11β-HSD2, permitting cortisol activation of mineralocorticoid receptors and potentially causing sodium retention, hypertension, edema, hypokalemia, metabolic alkalosis, arrhythmias, and suppression of renin and aldosterone. Risk increases with prolonged exposure and can be influenced by intestinal microbiota, renal/hepatic function, albumin concentration, age, and interacting medications. Licorice can also alter drug metabolism and should not be assumed pharmacologically inert when used with cancer therapy.</p>
<h3>Licorice Mechanistic Profile</h3>
<table>
<thead>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>HMGB1 inflammatory signaling</td>
<td>HMGB1 signaling ↓; inflammatory signaling ↓; proliferation ↓; migration ↓</td>
<td>HMGB1-mediated inflammation ↓</td>
<td>Suppresses inflammatory and tumor-promoting extracellular signaling</td>
<td>One of the most defensible licorice mechanisms because glycyrrhizin directly binds HMGB1. Particularly relevant to inflammation-associated tumor progression.</td>
</tr>
<tr>
<td>2</td>
<td>Cell cycle and proliferation</td>
<td>Proliferation ↓; Cyclin D1 ↓; CDK4 ↓; cell-cycle arrest ↑</td>
<td>↔ (context-dependent)</td>
<td>Restrains tumor-cell expansion</td>
<td>Demonstrated with whole licorice extracts and purified constituents. Exact checkpoint differs by preparation and tumor model.</td>
</tr>
<tr>
<td>3</td>
<td>Mitochondrial apoptosis and cell death</td>
<td>BAX ↑; BCL-2 ↓; caspase-3 ↑; apoptosis ↑; necrosis ↑ (model-dependent)</td>
<td>Apoptotic injury generally ↓ under oxidative or inflammatory stress (context-dependent)</td>
<td>Promotes tumor-cell death</td>
<td>Mode of death is extract-dependent. Recent whole-root extract studies demonstrate both apoptotic signatures and predominantly necrotic death in different cancer models.</td>
</tr>
<tr>
<td>4</td>
<td>EMT and metastatic signaling</td>
<td>EMT ↓; migration ↓; invasion ↓; N-cadherin ↓; E-cadherin ↑; SMAD2/3 signaling ↓</td>
<td>Pathological EMT ↓ (context-dependent)</td>
<td>Reduces invasive phenotype</td>
<td>Glycyrrhizin-HMGB1 inhibition is particularly relevant; effects have been demonstrated in prostate and epithelial models.</td>
</tr>
<tr>
<td>5</td>
<td>PI3K AKT mTOR and STAT3 survival signaling</td>
<td>PI3K ↓; AKT ↓; mTOR ↓; STAT3 ↓ (constituent-dependent)</td>
<td>↔ / mixed</td>
<td>Reduces survival and growth signaling</td>
<td>Strong evidence exists for several purified licorice flavonoids, but attribution to generic licorice extract should remain context-dependent because constituent composition varies markedly.</td>
</tr>
<tr>
<td>6</td>
<td>DNA damage response and NHEJ</td>
<td>HMGB1 ↓; NHEJ ↓; DNA fragmentation ↑; DNA-damage response altered</td>
<td>Not established</td>
<td>Reduces repair capacity and promotes tumor-cell injury</td>
<td>Recent colorectal-cancer evidence specifically implicates glycyrrhizin-mediated inhibition of HMGB1 and NHEJ-associated repair.</td>
</tr>
<tr>
<td>7</td>
<td>ROS and oxidative stress</td>
<td>ROS ↑ or ↓ (constituent-dependent); oxidative stress ↑ can promote apoptosis</td>
<td>ROS ↓; antioxidant defenses ↑</td>
<td>Bidirectional redox modulation</td>
<td>ROS ↑ should not be treated as a universal whole-licorice effect. Pro-oxidant tumor effects are particularly associated with selected chalcones/flavonoids, whereas antioxidant effects predominate in many normal-tissue models.</td>
</tr>
<tr>
<td>8</td>
<td>NRF2 antioxidant defense</td>
<td>Mixed (context-dependent)</td>
<td>NRF2 ↑; HO-1 ↑; SOD ↑; catalase ↑; GPx ↑</td>
<td>Protects normal tissues from oxidative injury</td>
<td>Secondary mechanism. Potentially beneficial for tissue protection, but persistent NRF2 activation in established cancers can theoretically support stress resistance; tumor context matters.</td>
</tr>
<tr>
<td>9</td>
<td>Angiogenesis and hypoxic signaling</td>
<td>VEGF ↓; HIF-1α ↓; CD31 ↓ (model-dependent)</td>
<td>↔ / not established</td>
<td>Reduces tumor vascular signaling</td>
<td>Preclinical and constituent-dependent; should not be interpreted as established systemic anti-angiogenic activity in humans.</td>
</tr>
<tr>
<td>10</td>
<td>Autophagy</td>
<td>Beclin-1 ↑; LC3-II/LC3-I ↑; p62 ↓ (model-dependent)</td>
<td>Mixed</td>
<td>Can contribute to growth suppression or cell death</td>
<td>Observed with selected licorice extracts and constituents. Functional consequence depends on whether autophagy is cytotoxic or adaptive in the specific model.</td>
</tr>
<tr>
<td>11</td>
<td>Chemosensitization</td>
<td>Antiproliferative effect ↑ with selected chemotherapy combinations</td>
<td>Toxicity modulation mixed</td>
<td>Potential adjunctive interaction</td>
<td>Preclinical combination studies include enhanced effects with doxorubicin/adriamycin. Human anticancer benefit has not been demonstrated, and pharmacokinetic interactions remain a concern.</td>
</tr>
<tr>
<td>12</td>
<td>Drug metabolism and CYP interactions</td>
<td>Drug exposure ↔ / altered</td>
<td>CYP activity ↓ or altered (species- and preparation-dependent)</td>
<td>Changes exposure to concomitant compounds</td>
<td>Clinically relevant because licorice preparations differ in constituent profiles. Interaction potential should be evaluated separately from anticancer mechanisms.</td>
</tr>
<tr>
<td>13</td>
<td>11β-HSD2 mineralocorticoid axis</td>
<td>Not a therapeutic anticancer mechanism</td>
<td>11β-HSD2 ↓; cortisol-mediated mineralocorticoid receptor activity ↑; potassium ↓; blood pressure ↑</td>
<td>Major systemic toxicity constraint</td>
<td>Driven principally by glycyrrhizin metabolites including glycyrrhetinic-acid derivatives. Clinically established and more relevant to achievable oral exposure than many in-vitro anticancer targets.</td>
</tr>
<tr>
<td>14</td>
<td>Clinical Translation Constraint</td>
<td>Direct extract exposure commonly exceeds achievable systemic levels</td>
<td>Systemic glycyrrhizin metabolites can produce dose-limiting endocrine and cardiovascular effects</td>
<td>Limits translation of in-vitro anticancer activity</td>
<td>Whole-extract composition, intestinal metabolism, low intact-glycyrrhizin exposure, species differences, CYP interactions, and pseudoaldosteronism make dose extrapolation particularly uncertain.</td>
</tr>
</tbody>
</table>