Dihydrocaffeic Acid / ROS Cancer Research Results

DHCA, Dihydrocaffeic Acid: Click to Expand ⟱
Features:
Phenolic acid found in plants, fungi and some foods. (grapes) Dihydrocaffeic acid is a phenolic acid. Chemically, it is the reduced (hydrogenated) form of caffeic acid.

-DHCA is known for its antioxidant properties. It can scavenge reactive oxygen species (ROS).
-DHCA has shown potential anti-inflammatory properties which might help reduce tumor-promoting inflammation in some contexts.
-important role as a gut-microbial metabolite of caffeic and chlorogenic acids

Dihydrocaffeic Acid — Dihydrocaffeic acid is a low-molecular-weight catechol-containing phenolic acid and a major gut-microbial metabolite of caffeic acid and chlorogenic acids. It is formally classified as a hydroxyphenylpropionic acid and dietary phenolic metabolite. Standard abbreviations are DHCA and, less specifically, HCA; DHCA is preferred because HCA is highly ambiguous. Its systematic name is 3-(3,4-dihydroxyphenyl)propanoic acid, and it is also called hydrocaffeic acid or 3,4-dihydroxyhydrocinnamic acid. It occurs in some plants and foods but is also generated in the colon after consumption of coffee, fruits, and other chlorogenic-acid-rich foods. The available cancer evidence concerns the free acid and should not be extrapolated to lipophilic dihydrocaffeate esters, which may be considerably more cytotoxic.

Primary mechanisms (ranked):

  1. Dose-dependent antiproliferative and cytotoxic activity in selected cancer cell lines, with the strongest reported sensitivity in PC-3 prostate, MCF-7 breast, and HCT-116 colorectal cancer cells; the immediate molecular target remains unidentified.
  2. Redox-dependent cytotoxicity at high concentrations, involving increased oxidative stress and probable mitochondrial dysfunction in susceptible cancer cells, particularly when combined with sulforaphane or curcumin.
  3. Enhancement of phytochemical combination activity, including synergistic suppression of colorectal cancer-cell viability by DHCA-containing combinations.
  4. Direct catechol-mediated radical scavenging and suppression of stress-induced ROS at physiologically relevant low-micromolar concentrations, predominantly producing cytoprotective rather than anticancer effects.
  5. Context-dependent anti-inflammatory and epigenetic modulation, including reduced DNMT1 expression and altered IL-6 gene methylation in immune-cell and mouse models; direct suppression of inflammatory cytokines has not been reproduced consistently across cell models.

Bioavailability / PK relevance: DHCA is a biologically relevant circulating and urinary host–microbiome co-metabolite of chlorogenic acids. Free DHCA and especially its sulfate and glucuronide conjugates appear several hours after ingestion, consistent with colonic microbial formation and subsequent phase-II metabolism. Reported human plasma exposure after ordinary food or coffee intake is generally in the nanomolar to low-micromolar range, with marked interindividual variability related to dose, microbiota, absorption, and conjugation. Rapid metabolism and predominantly conjugated systemic exposure limit direct translation of experiments using high concentrations of unconjugated DHCA.

In-vitro vs systemic exposure relevance: Direct cancer-cell CC50 values for free DHCA are approximately 162–529 µM, whereas protective antioxidant effects have been demonstrated at approximately 0.2–10 µM. The concentrations required for direct monotherapy-like cancer cytotoxicity therefore substantially exceed typical circulating exposure after dietary intake. Lower-concentration combination effects may be more experimentally relevant, but they remain preclinical and have not established clinically achievable intratumoral activity.

Clinical evidence status: Preclinical only for cancer. Evidence consists primarily of cell-viability experiments and phytochemical-combination studies, without validated tumor targets, animal antitumor efficacy for isolated DHCA, controlled human cancer trials, or an approved therapeutic formulation. Human studies have measured DHCA as a dietary or botanical-product metabolite, not as an established anticancer treatment. There is no FDA, EMA, or Health Canada approval for DHCA as a cancer drug or adjunct.



Mechanistic Effects of Dihydrocaffeic Acid

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Cell viability and proliferation ↓ viability and proliferation (dose-dependent) (high concentration only) ↓ viability at higher concentrations G Selective but modest cytotoxicity in some cancer models Reported CC50 values were approximately 162 µM in PC-3, 230 µM in HCT-116, 307 µM in MCF-7, 501 µM in normal HDFa fibroblasts, and 529 µM in HepG2. HepG2 cells were less sensitive than normal fibroblasts, demonstrating that selectivity is model-dependent.
2 Oxidative stress threshold ↑ ROS and oxidative damage (high concentration only) (context-dependent) ↓ stress-induced ROS at low micromolar exposure R G Concentration-dependent redox hormesis Low exposure is generally antioxidant and cytoprotective, whereas sufficiently high exposure or selected combinations can exceed cancer-cell antioxidant capacity. ROS-mediated cancer toxicity remains proposed rather than fully mapped for DHCA alone.
3 Mitochondrial function ↓ mitochondrial function or membrane polarization (context-dependent) (high concentration only) Protection from oxidant-induced mitochondrial and macromolecular injury R G Potential mitochondrial contribution to cytotoxicity Mitochondrial disruption is most strongly supported in high-oxidative-stress combination experiments. A defined DHCA mitochondrial binding target or MPTP mechanism has not been established.
4 Combination phytochemical response ↑ cytotoxic response with sulforaphane and curcumin (dose-dependent) Insufficient comparative evidence G Synergistic or additive growth inhibition DHCA-containing combinations reduced HCT-116 and HT-29 colorectal cancer-cell viability more strongly than selected single compounds. This does not establish synergy with conventional chemotherapy.
5 Apoptotic cell death ↑ apoptosis or nonviable-cell fraction (context-dependent) ↓ oxidant-induced apoptosis under protective conditions G Execution of redox-associated cell death Apoptosis has been reported primarily in combination experiments and with DHCA derivatives. Bax, BCL-2, caspase, or death-receptor regulation should not be entered as established direct targets of unmodified DHCA without compound-specific evidence.
6 ROS scavenging and glutathione homeostasis ↓ externally induced ROS at low micromolar exposure ↓ ROS and macromolecular oxidation; ↔ or slight ↑ GSH R G Antioxidant and cytoprotective activity DHCA at approximately 0.2–10 µM protects oxidatively challenged hepatic and other normal-cell models. This effect could theoretically protect malignant cells or reduce ROS-dependent treatment effects in some contexts.
7 DNMT1 and IL-6 epigenetic regulation Uncertain ↓ DNMT1 and ↓ IL-6 in immune and inflammatory models G Anti-inflammatory epigenetic modulation DHCA reduced DNMT1 expression and altered IL-6 intragenic methylation in mouse immune-cell and stress models. Cancer-cell relevance and direction of therapeutic leverage remain unvalidated.
8 Inflammatory cytokine response Uncertain ↓ inflammatory signaling (model-dependent) G Context-dependent control of inflammatory tone Although DHCA reduced IL-6 in selected immune models, 0.5–10 µM DHCA did not significantly lower IL-6, IL-8, MCP-1, or MIP-1β in TNF-α-challenged HepG2 cells. Generalized cytokine suppression should therefore not be assumed.
9 NRF2 antioxidant response Uncertain Possible ↑ NRF2-linked antioxidant defenses (context-dependent) R G Secondary cytoprotective signaling DHCA can preserve glutathione and normalize antioxidant-enzyme activity, but direct NRF2 activation by free DHCA is not sufficiently established to designate NRF2 as a primary cancer target.
10 Clinical Translation Constraint Required cytotoxic exposure greatly exceeds typical dietary plasma exposure Systemic exposure is predominantly low and extensively conjugated G Limited direct anticancer translation Key constraints are high in-vitro CC50 values, gut-microbiome variability, delayed formation, sulfate and glucuronide conjugation, uncertain tumor penetration, incomplete toxicology, lack of animal monotherapy efficacy, and absence of cancer trials.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.
-mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related)
ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2 inhibition: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α inhibition: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1 inhibition:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK activation: regulates energy metabolism and can increase ROS levels when activated.
• mTOR inhibition: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90 inhibition: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Mevalonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day, -Dipyridamole typically 200mg 2x/day Combined effect research
-Lycopene typically 100mg/day range (note debatable as it mainly lowers NRF2)

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy 
ROS-Inducing Interventions in Cancer — Canonical + Mechanistic Reference
-generated from AI and Cancer database
ROS rating:  +++ strong | ++ moderate | + weak | ± mixed | 0 none
NRF2:        ↓ suppressed | ↑ activated | ± mixed | 0 none
Conditions:  [D] dose  [Fe] metal  [M] metabolic  [O₂] oxygen
             [L] light [F] formulation [T] tumor-type [C] combination




Item ROS↑ NRF2 Condition Mechanism Class Remarks 



ROS">Piperlongumine
+++ ↓ [D][T] ROS-dominant






ROS">Shikonin
+++↓/±[D][T]ROS-dominant






ROS">Vitamin K3 (menadione)
+++↓[D]ROS-dominant






ROS">Copper (ionic / nano)
+++↓[Fe][F]ROS-dominant






ROS">Sodium Selenite
+++↓[D]ROS-dominant






ROS">Juglone
+++↓[D]ROS-dominant






ROS">Auranofin
+++↓[D]ROS-dominant






ROS">Photodynamic Therapy (PDT)
+++0[L][O₂]ROS-dominant






ROS">Radiotherapy / Radiation
+++0[O₂]ROS-dominant






ROS">Doxorubicin
+++↓[D]ROS-dominant






ROS">Cisplatin
++↓[D][T]ROS-dominant






ROS">Salinomycin
++↓[D][T]ROS-dominant






ROS">Artemisinin / DHA
++↓[Fe][T]ROS-dominant






ROS">Sulfasalazine
++↓[C][T]ROS-dominant






ROS">FMD / fasting
++↓[M][C][O₂]ROS-dominant






ROS">Vitamin C (pharmacologic)
++↓[Fe][D]ROS-dominant






ROS">Silver nanoparticles
++±[F][D]ROS-dominant






ROS">Gambogic acid
++↓[D][T]ROS-dominant






ROS">Parthenolide
++↓[D][T]ROS-dominant






ROS">Plumbagin
++↓[D]ROS-dominant






ROS">Allicin
++↓[D]ROS-dominant






ROS">Ashwagandha (Withaferin A)
++↓[D][T]ROS-dominant






ROS">Berberine
++↓[D][M]ROS-dominant






ROS">PEITC
++↓[D][C]ROS-dominant






ROS">Methionine restriction
+↓[M][C][T]ROS-secondary






ROS">DCA
+±[M][T]ROS-secondary






ROS">Capsaicin
+±[D][T]ROS-secondary






ROS">Galloflavin
+0[D]ROS-secondary






ROS">Piperine
+±[D][F]ROS-secondary






ROS">Propyl gallate
+↓[D]ROS-secondary






ROS">Scoulerine
+?[D][T]ROS-secondary






ROS">Thymoquinone
±±[D][T]Dual redox






ROS">Emodin
±±[D][T]Dual redox






ROS">Alpha-lipoic acid (ALA)
±↑[D][M]NRF2-dominant






ROS">Curcumin
±↑/↓[D][F]NRF2-dominant






ROS">EGCG
±↑/↓[D][O₂]NRF2-dominant






ROS">Quercetin
±↑/↓[D][Fe]NRF2-dominant






ROS">Resveratrol
±↑[D][M]NRF2-dominant






ROS">Sulforaphane
±↑↑[D]NRF2-dominant






ROS">Lycopene
0↑—Antioxidant






ROS">Rosmarinic acid
0↑—Antioxidant






ROS">Citrate
00—Neutral


Scientific Papers found: Click to Expand⟱
6720- CUR,  SFN,  DHCA,    Synergistic Combinations of Curcumin, Sulforaphane, and Dihydrocaffeic Acid against Human Colon Cancer Cells
- in-vitro, Colon, HT29 - in-vitro, Colon, Caco-2 - in-vitro, Nor, FHC
selectivity↑, TumCCA↑, Apoptosis↑, ROS↑, MMP↓, ROS⇅, ERK↑, JNK↑, MAPK↑, P21↑, cycD1/CCND1↓, Cyt‑c↑,
6719- DHCA,    Anticancer potential of dihydrocaffeic acid: a chlorogenic acid metabolite
- in-vitro, BC, MCF7 - in-vitro, Pca, PC3 - in-vitro, Liver, HepG2 - in-vitro, CRC, HCT116 - in-vitro, Nor, HDFa
*antiOx↑, *cardioP↑, *neuroP↑, selectivity↑, selectivity↓, TumCCA↑, ROS↑, mtDam↑,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 2,   ROS⇅, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

MMP↓, 1,   mtDam↑, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,   Cyt‑c↑, 1,   JNK↑, 1,   MAPK↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

cycD1/CCND1↓, 1,   P21↑, 1,   TumCCA↑, 2,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

ERK↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

selectivity↓, 1,   selectivity↑, 2,  
Total Targets: 14

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

antiOx↑, 1,  

Functional Outcomes(tgid=23) ⓘ

cardioP↑, 1,   neuroP↑, 1,  
Total Targets: 3

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
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

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:71  Target#:275  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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