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| Hydroxycinnamic acid 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 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) -Ferulic acid and p‐coumaric acid are naturally occurring hydroxycinnamic acids found in many plant-based foods (such as whole grains, fruits, and vegetables) 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. Summary: -HCAs are classically antioxidant -Such as caffeic acid, ferulic acid, and sinapic acid (SA) -May increase sensitivity to chemotherapy -Bioavailability is problem. Formulation strategies (e.g., liposomal or encapsulated forms) are investigated to improve systemic exposure. -Propolis has caffeic acid (Caffeic acid (0.639–4.172 mg/g propolis) -SA at higher concentrations may acts as a potent pro-oxidant agent -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 -Combination of caffeic acid and endogenous copper ions can result in oxidative damage -Ferulic Acid (abundant in whole grains,popcorn): upregulate apoptotic protein and downregulate anti-apoptotic protein.upregulating (BAX), (p53), (CYCS) and downregulating (Bcl-2),
Time-Scale Flag (TSF): P / R / G
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| Source: TCGA |
| Type: Antiapoptotic |
| Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response. -One way to estimate Nrf2 induction is through the expression of NQO1. NQO1, the most potent inducer: SFN 0.2 μM, quercetin (2.5 μM), curcumin (2.7 μM), Silymarin (3.6 μM), tamoxifen (5.9 μM), genistein (6.2 μM ), beta-carotene (7.2μM), lutein (17 μM), resveratrol (21 μM), indol-3-carbinol (50 μM), chlorophyll (250 μM), alpha-cryptoxanthin (1.8 mM), and zeaxanthin (2.2 mM) 1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects. 2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death. 3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress -In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies. -Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate. Decreased Nrf2 expression: Skine, Liver, Pancreatic. -Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer - "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1. Nrf2 Inhibitors and Activators Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api - potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue. – In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis. – In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity. – This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming. – Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies. – High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types. – While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression. NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS). -Brusatol: most cited natural inhibitors of Nrf2. -Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent. -Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent . -Oridonin: -Wogonin: although its effects might be cell‑ and dose‑specific. - Withaferin A |
| 1638- | HCAs, | Anticancer potential of hydroxycinnamic acids: mechanisms, bioavailability, and therapeutic applications |
| - | Review, | Nor, | NA |
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
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