Description: <b>Copper</b><br>
Metal<br>
Copper levels are considerably elevated in various malignancies.<br>
Copper [Cu(II)] is a transition and trace element in living organisms. It increases reactive oxygen species (ROS) and free-radical generation that might damage biomolecules like DNA, proteins, and lipids.<br>
<br>
Copper (dietary/physiology) ≠ copper-loading therapeutics ≠ copper nanoparticles.<br>
For Cu nanoparticles, the dominant and most reproducible theme is toxicity via ROS → mitochondrial damage/genotoxicity, not clean tumor selectivity.<br>
- Copper acts as a critical cofactor for numerous enzymes involved in redox reactions, energy production, and connective tissue formation.<br>
- Increased copper levels in the tumor microenvironment can enhance angiogenic signaling and thus supply the tumor with necessary oxygen and nutrients, facilitating tumor growth and metastasis.<br>
- Copper can participate in redox cycling reactions, similar to the Fenton reaction, leading to the production of reactive oxygen species (ROS).<br>
- Cancer cells often exhibit altered copper homeostasis, with some studies showing elevated copper levels in tumor tissues relative to normal tissues.<br>
<br>
Two main approaches are:<br>
- Copper Chelation: Drugs that bind copper (chelators) can reduce the bioavailability of copper, potentially inhibiting angiogenesis and other copper-dependent tumor processes.<br>
- Copper Ionophores: These agents facilitate the transport of copper into cancer cells to induce cytotoxicity by elevating intracellular copper levels beyond a tolerable threshold, leading to cell death.<br>
<br>
- Depletion of glutathione and stimulation of lipid peroxidation, catalase and superoxide dismutase.<br>
- Studies have shown that the level of copper in tumour cells and blood serum from cancer patients is elevated, and the conclusion is that cancer cells need more copper than healthy cells. (but also sometimes depleted).<br>
- Copper is a double-edged sword, maintaining normal cell development and promoting tumor development.<br>
- Tumor tissue has a higher demand for copper and is more susceptible to copper homeostasis, copper may modulate cancer cell survival through reactive oxygen species (ROS) excessive accumulation, proteasome inhibition and anti-angiogenesis.<br>
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Natural Product: Cu, Copper (ion biology)<br>
<!-- Copper (Cu) — Cancer/Oncology-Focused Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Cuproptosis (copper-triggered mitochondrial cell death)</td>
<td>Cu accumulation → binding to lipoylated TCA proteins → aggregation; Fe–S proteins ↓; proteotoxic stress ↑</td>
<td>Tight copper homeostasis usually prevents this</td>
<td>R, G</td>
<td>Regulated cell death (mitochondria-linked)</td>
<td>Cuproptosis is a distinct copper-dependent death pathway tied to mitochondrial metabolism and lipoylated TCA components. :contentReference[oaicite:0]{index=0}</td>
</tr>
<tr>
<td>2</td>
<td>Copper homeostasis machinery (transport/chaperones)</td>
<td>Copper trafficking affects tumor programs (growth/metastasis; context)</td>
<td>Essential micronutrient; homeostasis prevents toxicity</td>
<td>R, G</td>
<td>Homeostasis / signaling coupling</td>
<td>Copper import/export and chaperones couple copper availability to signaling and phenotype; dysregulation is increasingly discussed in cancer biology. :contentReference[oaicite:1]{index=1}</td>
</tr>
<tr>
<td>3</td>
<td>Angiogenesis support (copper-dependent tumor vascularization)</td>
<td>Pro-angiogenic tone supported by copper availability (context)</td>
<td>Physiologic angiogenesis/wound repair support</td>
<td>G</td>
<td>Vascular program modulation</td>
<td>Copper deficiency/chelation has been reported to impair tumor angiogenesis in preclinical/clinical contexts. :contentReference[oaicite:2]{index=2}</td>
</tr>
<tr>
<td>4</td>
<td>LOX/LOXL family (ECM remodeling; copper-dependent enzymes)</td>
<td>ECM crosslinking / invasion-metastasis programs ↑ (context)</td>
<td>Normal ECM maturation and tissue repair</td>
<td>G</td>
<td>Microenvironment remodeling</td>
<td>LOX enzymes are copper-dependent and implicated in tumor stroma remodeling and metastatic niche biology. :contentReference[oaicite:3]{index=3}</td>
</tr>
<tr>
<td>5</td>
<td>ROS / redox chemistry (Cu redox cycling)</td>
<td>Oxidative stress ↑ (context); DNA/protein damage ↑</td>
<td>Redox enzyme cofactor; excess is toxic</td>
<td>P, R, G</td>
<td>Stress amplification (conditional)</td>
<td>Copper can catalyze redox reactions; whether this is tumor-selective depends on copper handling, antioxidants, and exposure context.</td>
</tr>
<tr>
<td>6</td>
<td>Copper ionophores / copper-loading strategies (research/therapy concept)</td>
<td>Intracellular Cu ↑ → stress/death programs ↑ (context)</td>
<td>—</td>
<td>R, G</td>
<td>Therapeutic lever (conceptual)</td>
<td>Reviews discuss copper ionophores as tools to drive copper accumulation and explore cuproptosis/ROS mechanisms; clinical positioning varies. :contentReference[oaicite:4]{index=4}</td>
</tr>
<tr>
<td>7</td>
<td>Copper chelation (anti-angiogenic / microenvironment strategy)</td>
<td>Angiogenesis and tumor progression pressure ↓ (context)</td>
<td>Risk of deficiency if excessive</td>
<td>G</td>
<td>Translation/strategy axis</td>
<td>Tetrathiomolybdate and related chelation strategies have been studied clinically as anti-angiogenic approaches. :contentReference[oaicite:5]{index=5}</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (rapid redox interactions)</li>
<li><b>R</b>: 30 min–3 hr (acute mitochondrial/proteotoxic stress signaling)</li>
<li><b>G</b>: >3 hr (gene-regulatory adaptation and phenotype outcomes)</li>
</ul>
<br>
Copper Nanoparticles: CuNP / CuO-NP (tox + “anticancer” claims are mostly preclinical)<br>
<!-- Copper Nanoparticles (CuNP / CuO-NP) — Preclinical Cancer + Toxicology Time-Scale Flagged Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Axis</th>
<th>Cell/Tumor Context</th>
<th>Whole-Body / Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Oxidative stress (ROS generation) + antioxidant depletion</td>
<td>ROS ↑; lipid peroxidation ↑; DNA damage ↑ (reported)</td>
<td>Liver/kidney oxidative injury risk ↑ in animal studies</td>
<td>P, R, G</td>
<td>Primary toxicity driver</td>
<td>CuO nanoparticles are widely reported to cause cytotoxicity primarily via oxidative stress leading to genotoxicity. :contentReference[oaicite:6]{index=6}</td>
</tr>
<tr>
<td>2</td>
<td>Mitochondrial dysfunction</td>
<td>ΔΨm ↓; ATP ↓; apoptosis signaling ↑ (reported)</td>
<td>Organ toxicity links include mitochondrial impairment</td>
<td>R, G</td>
<td>Energy failure / apoptosis coupling</td>
<td>Mitochondria-mediated apoptosis has been reported with CuO NPs in cell models (e.g., HepG2). :contentReference[oaicite:7]{index=7}</td>
</tr>
<tr>
<td>3</td>
<td>Inflammation / immune activation</td>
<td>Inflammatory signaling ↑ (context)</td>
<td>Inflammation contributes to organ injury in vivo</td>
<td>R, G</td>
<td>Tissue injury amplification</td>
<td>Sub-chronic exposure reviews describe inflammation as part of CuNP/CuO-NP toxicity patterns. :contentReference[oaicite:8]{index=8}</td>
</tr>
<tr>
<td>4</td>
<td>Genotoxicity</td>
<td>DNA strand breaks ↑; chromosomal damage ↑ (reported)</td>
<td>Potential long-term risk signal (model-dependent)</td>
<td>R, G</td>
<td>Genome damage</td>
<td>Often downstream of ROS; repeatedly reported across CuO NP toxicity literature. :contentReference[oaicite:9]{index=9}</td>
</tr>
<tr>
<td>5</td>
<td>“Anticancer” cytotoxicity claims (preclinical)</td>
<td>Viability ↓ in various cell lines (often at high concentrations)</td>
<td>Translation limited by toxicity and exposure constraints</td>
<td>G</td>
<td>Non-selective cytotoxicity risk</td>
<td>Many studies show tumor cell killing, but often at concentrations that also harm normal cells; selectivity is a major issue. :contentReference[oaicite:10]{index=10}</td>
</tr>
<tr>
<td>6</td>
<td>Reproductive/developmental toxicity signals (animal models)</td>
<td>—</td>
<td>Reported reproductive system impacts in animal studies</td>
<td>G</td>
<td>Safety constraint</td>
<td>Recent studies discuss reproductive toxicity and mitochondrial injury in germline cells with CuO NPs. :contentReference[oaicite:11]{index=11}</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (rapid ROS/redox interactions at particle surfaces)</li>
<li><b>R</b>: 30 min–3 hr (mitochondrial stress + inflammatory signaling)</li>
<li><b>G</b>: >3 hr (genotoxicity, apoptosis, organ-level outcomes)</li>
</ul>