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| Formononetin is an O-methylated isoflavone. -Ononin is formononetin-7-O-β-D-glucoside, meaning formononetin with a glucose attached at the 7-position. Found in several plant sources, including: Red Clover (Trifolium pratense): Astragalus membranaceus: Other Leguminous Plants: -Various plants in the legume family (Fabaceae) may also contain formononetin, although the levels and bioavailability can differ depending on the plant species and extraction methods. Pathways: PI3K/Akt Pathway: formononetin may inhibit the phosphorylation of Akt (MAPK) Pathway: may modulate components of the MAPK pathway STAT3 Signaling Pathway: formononetin can downregulate STAT3 activity NF-κB Pathway: modulating NF-κB activation Apoptotic Pathways: via mitochondrial-dependent pathways, enhancing caspase activation Induce cell cycle arrest at different checkpoints (e.g., G1 or G2/M phases) Formononetin, a naturally occurring isoflavone found in red clover, Astragalus membranaceus, and other leguminous plants, shows promise as an anticancer agent. Its ability to modulate key signaling pathways—including PI3K/Akt, MAPK, STAT3, NF-κB, and apoptotic and cell cycle regulatory mechanisms—suggests a multifaceted potential in cancer prevention and therapy. Formononetin — Formononetin is a naturally occurring O-methylated isoflavone and phytoestrogen found primarily in red clover, Astragalus membranaceus, licorice, kudzu, and other Fabaceae plants. It is classified as a plant-derived isoflavonoid small molecule and is commonly abbreviated FMN, FNT, FT, or Form. Formononetin is also produced from its glycoside ononin and is extensively converted in vivo to daidzein and phase-II conjugates. Its anticancer activity remains experimental and is complicated by concentration-dependent estrogen-receptor signaling, limited aqueous solubility, rapid metabolism, and comparatively low systemic exposure to unconjugated parent compound. Primary mechanisms (ranked):
Bioavailability / PK relevance: Native formononetin has poor water solubility, substantial intestinal and hepatic first-pass metabolism, rapid glucuronidation and sulfation, and extensive O-demethylation to daidzein. Rat oral bioavailability has been reported at approximately 22%, but this does not establish comparable human exposure. Free parent formononetin generally represents only a small fraction of circulating total isoflavones. Phospholipid, nanoparticle, lipid, and bioenhancer formulations can increase exposure in animals but are not validated cancer treatments. In-vitro vs systemic exposure relevance: Many anticancer studies use approximately 20–100 µM formononetin, whereas exposure to unconjugated parent compound after ordinary oral red-clover or dietary-isoflavone intake is generally much lower. Consequently, many direct cytotoxic, ROS-generating, STAT-inhibitory, and apoptosis-inducing findings occur at concentrations unlikely to be achieved systemically with conventional oral preparations. Lower concentrations may instead produce estrogenic or proliferative effects in ERα-positive cells, creating a clinically important biphasic-response concern. Clinical evidence status: Preclinical. Evidence includes cancer-cell experiments and multiple murine xenograft or carcinogenesis models. No established formononetin monotherapy or adjunctive cancer regimen is supported by completed randomized clinical trials, and formononetin is not an approved anticancer drug. Human trials involving red-clover isoflavone mixtures address menopausal, vascular, or bone outcomes rather than cancer treatment and cannot be attributed specifically to formononetin. Safety considerations: Human safety data for purified formononetin are limited. Its ERα agonist and phytoestrogen properties warrant caution in estrogen-sensitive malignancies and in patients using endocrine therapies. Experimental studies demonstrate concentration-dependent stimulation of ERα-positive breast-cancer cells at low micromolar concentrations and inhibition at higher concentrations. Potential interactions may also arise through drug-efflux transporters, CYP enzymes, glucuronidation pathways, anticoagulant drugs, or combination chemotherapy. Long-term reproductive, endocrine, hepatic, and oncologic safety of pharmacological-dose purified formononetin remains unresolved. Formononetin Mechanistic Profile
P: 0–30 min R: 30 min–3 hr G: >3 hr |
| 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 |
| 6981- | Form, | Formononetin: a review of its source, pharmacology, drug combination, toxicity, derivatives, and drug delivery systems |
| - | Review, | Var, | NA | - | Review, | AD, | NA | - | Review, | PSA, | 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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