Dihydrocaffeic Acid / Cyt‑c 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
Cyt‑c, cyt-c Release into Cytosol: Click to Expand ⟱
Source:
Type:
Cytochrome c
** The term "release of cytochrome c" ** an increase in level for the cytosol.
Small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis.

The term "release of cytochrome c" refers to a critical step in the process of programmed cell death, also known as apoptosis.
In its new location—the cytosol—cytochrome c participates in the apoptotic signaling pathway by helping to form the apoptosome, which activates caspases that execute cell death.
Cytochrome c is a small protein normally located in the mitochondrial intermembrane space. Its primary role in healthy cells is to participate in the electron transport chain, a process that helps produce energy (ATP) through oxidative phosphorylation.
Mitochondrial outer membrane permeability leads to the release of cytochrome c from the mitochondria into the cytosol.
The release of cytochrome c is a pivotal event in apoptosis where cytochrome c moves from the mitochondria to the cytosol, initiating a chain reaction that leads to programmed cell death.

On the one hand, cytochrome c can promote cancer cell survival and proliferation by regulating the activity of various signaling pathways, such as the PI3K/AKT pathway. This can lead to increased cell growth and resistance to apoptosis, which are hallmarks of cancer.
On the other hand, cytochrome c can also induce apoptosis in cancer cells by interacting with other proteins, such as Apaf-1 and caspase-9. This can lead to the activation of the intrinsic apoptotic pathway, which can result in the death of cancer cells.
Overexpressed in Breast, Lung, Colon, and Prostrate.
Underexpressed in Ovarian, and Pancreatic.
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↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 1,   ROS⇅, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

MMP↓, 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↑, 1,  

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

ERK↑, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

selectivity↑, 1,  
Total Targets: 12

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Cyt‑c, cyt-c Release into Cytosol
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#:77  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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