Description: <b>Hydroxycinnamic acid</b> compounds (p-coumaric, caffeic acid (CA), ferulic acid) occur most frequently as simple esters with hydroxy carboxylic acids or glucose, while the hydroxybenzoic acid compounds (p-hydroxybenzoic, gallic acid, ellagic acid) are present mainly in the form of glucosides. https://www.sciencedirect.com/topics/chemistry/hydroxycinnamic-acid<br>
Hydroxycinnamic acids (HCAs) are plant-derived phenolic acids (including caffeic, ferulic, p-coumaric, and sinapic acids) with documented antioxidant, anti-inflammatory (NF-κB↓), and context-dependent anticancer effects in cellular and preclinical models. Mechanistic themes include activation of the Nrf2/ARE antioxidant response, suppression of pro-inflammatory and survival pathways (such as NF-κB and PI3K/AKT), modulation of MAPK signaling, and downstream effects on cell-cycle, apoptosis, invasion, and angiogenesis. Oral exposure is influenced by rapid metabolism (phase II conjugates) and food matrix effects, which affects systemic bioavailability and translational relevance. Biological effects vary by specific hydroxycinnamic derivative and its conjugated/esterified form. (Caffeic acid ≠ ferulic acid ≠ sinapic acid)<br>
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-Ferulic acid and p‐coumaric acid are naturally occurring hydroxycinnamic acids found in many plant-based foods (such as whole grains, fruits, and vegetables)<br>
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CA showed pro-oxidant potential due to its ability to interact with metals like copper, inducing lipid peroxidation and causing DNA damage within tumor cells through either oxidation or covalent adduct formation.<br>
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Summary:<br>
-HCAs are classically antioxidant<br>
-Such as caffeic acid, ferulic acid, and sinapic acid (SA)<br>
-May increase sensitivity to
<a href="https://nestronics.ca/dbx/tbResList.php?qv=95&tsv=1106&wNotes=0">chemotherapy</a><br>
-Bioavailability is problem. Formulation strategies (e.g., liposomal or encapsulated forms) are investigated to improve systemic exposure.<br>
-Propolis has caffeic acid (Caffeic acid (0.639–4.172 mg/g propolis)<br>
-SA at higher concentrations may acts as a potent pro-oxidant agent<br>
-SA may act in collaboration with other chemotherapeutic agents to improve treatment sensitivity.
-Co-administration of caffeic acid or CAPE with other anti-tumor compounds (e.g., gallic acid) has shown additive or synergistic effects in selected models<br>
-Combination of caffeic acid and endogenous copper ions can result in oxidative damage<br>
-Ferulic Acid (abundant in whole grains,popcorn): upregulate apoptotic protein and downregulate anti-apoptotic protein.upregulating (BAX), (p53), (CYCS) and downregulating (Bcl-2),<br>
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<!-- Hydroxycinnamic Acid (HCA) — Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Nrf2/ARE antioxidant response (Keap1-Nrf2-HO-1)</td>
<td>Stress adaptation modulation (context-dependent)</td>
<td>Nrf2 ↑; HO-1 & GSH systems ↑</td>
<td>R, G</td>
<td>Endogenous antioxidant upshift</td>
<td>Hydroxycinnamic acids commonly promote Nrf2 nuclear translocation and elevate antioxidant defense enzymes; this is one of the most consistent in vivo correlates.</td>
</tr>
<tr>
<td>2</td>
<td>NF-κB inflammatory transcription</td>
<td>NF-κB ↓; pro-inflammatory cytokine programs ↓ (reported)</td>
<td>Inflammation tone ↓; protective in injury models</td>
<td>R, G</td>
<td>Anti-inflammatory signaling</td>
<td>Hydroxycinnamic acids are widely reported to reduce NF-κB activity and downstream cytokine expression across inflammation and tumor models.</td>
</tr>
<tr>
<td>3</td>
<td>ROS / oxidative stress modulation</td>
<td>Oxidative stress ↓ (often); ROS direction variable</td>
<td>Oxidative injury ↓ in stress models</td>
<td>P, R, G</td>
<td>Redox buffering (context-dependent)</td>
<td>These acids are generally antioxidant, but in certain cancer models or at higher concentrations they may affect redox dynamics differentially.</td>
</tr>
<tr>
<td>4</td>
<td>Cell-cycle checkpoints (Cyclin D1/CDK4/6; checkpoints)</td>
<td>Cell-cycle arrest ↑ (reported); Cyclin/CDKs ↓</td>
<td>↔</td>
<td>G</td>
<td>Cytostasis</td>
<td>Largely late phenotype outcome linked to signaling changes.</td>
</tr>
<tr>
<td>5</td>
<td>Apoptosis (intrinsic/mitochondrial & caspase-linked)</td>
<td>Apoptosis ↑; caspase activation ↑ (reported)</td>
<td>↔ (less activation in normal contexts)</td>
<td>G</td>
<td>Cell death execution</td>
<td>Dependent on model and oxidative stress context; not as “direct” as classical mitochondrial toxins.</td>
</tr>
<tr>
<td>6</td>
<td>MAPK re-wiring (ERK / JNK / p38)</td>
<td>MAPK modulation (context-dependent)</td>
<td>↔</td>
<td>P, R, G</td>
<td>Signal reprogramming</td>
<td>Directions vary by tissue, stress levels, and derivative; avoid fixed arrows for all MAPKs unless model-specific evidence is provided.</td>
</tr>
<tr>
<td>7</td>
<td>PI3K → AKT (± mTOR) survival axis</td>
<td>PI3K/AKT modulation (reported)</td>
<td>↔</td>
<td>R, G</td>
<td>Survival/growth modulation</td>
<td>Often reported as downstream of NF-κB suppression and redox buffering.</td>
</tr>
<tr>
<td>8</td>
<td>Invasion / metastasis programs (MMPs / EMT)</td>
<td>MMPs ↓; migration-invasion ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Anti-invasive phenotype</td>
<td>Observed as downstream phenotypes; direction depends on specific hydroxycinnamic acid derivative.</td>
</tr>
<tr>
<td>9</td>
<td>Angiogenesis signaling (VEGF & angiogenic outputs)</td>
<td>VEGF ↓; angiogenesis markers ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Anti-angiogenic support</td>
<td>Later phenotype marker; linked to reduced pro-inflammatory and survival signaling.</td>
</tr>
<tr>
<td>10</td>
<td>Bioavailability / metabolism constraint (conjugation; food matrix dependence)</td>
<td>Systemic exposure variable; rapid conjugation</td>
<td>—</td>
<td>—</td>
<td>Translation constraint</td>
<td>Hydroxycinnamic acids are absorbed but rapidly metabolized (phase II conjugates); food matrix alters bioaccessibility and systemic exposure.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (primary/rapid effects; early redox interactions)</li>
<li><b>R</b>: 30 min–3 hr (acute stress-response + transcription signaling shifts)</li>
<li><b>G</b>: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)</li>
</ul>