Fused Polypore

Metadata

Regulatory Status

United States

• Dietary supplement: Not marketed as a dietary supplement. Grifolin is available as a research chemical from specialty suppliers.
• FDA GRAS status: No GRAS determination.
• Edibility: Considered edible but not choice; the flesh is tough and has a somewhat acrid or bitter taste when raw. Not widely consumed as food.

European Union

• Novel food: Not authorized. No history of significant food use in the EU prior to 1997, though the mushroom occurs naturally in European coniferous forests.
• EMA/HMPC: No monograph exists.
• Status: Primarily of research interest for its bioactive compounds.

China and Japan

• China: Not listed in the Chinese Pharmacopoeia. Studied as a source of bioactive natural products in Chinese pharmaceutical research.
• Japan: Not recognized in Japanese pharmaceutical or food regulations.

Conditions & Indications

Primary: Antitumor Activity (Preclinical Evidence Only)

• Cancer cell growth inhibition: Grifolin inhibits proliferation and induces apoptosis in multiple human cancer cell lines, including nasopharyngeal carcinoma, osteosarcoma, ovarian cancer, breast cancer, and colon cancer cells. The effects are dose- and time-dependent.
• KRAS suppression in colon cancer: Grifolin, neogrifolin, and confluentin suppress KRAS oncogene expression in human colon cancer cells, a novel bioactivity mechanism for these farnesyl phenols.
• Cell-cycle arrest: Grifolin induces G1 phase cell-cycle arrest through ERK1/2 pathway inhibition and upregulation of the cyclin-dependent kinase inhibitor p19INK4D.

Secondary: Antiparasitic/Anthelmintic Activity (Preclinical Evidence)

• Nematode activity: Grifolin and neogrifolin demonstrate anthelmintic activity against Caenorhabditis elegans and parasitic nematodes. Prenyl-2-orcinol and geranylgeranyl-2-orcinol showed promising activity against newly transformed schistosomula of Schistosoma mansoni and parasitic nematodes including Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum.

Emerging/Preclinical

• Anti-inflammatory: Grifolin derivatives from related Albatrellus species (A. caeruleoporus) inhibit nitric oxide production in RAW 264.7 macrophage cells, suggesting anti-inflammatory potential.
• Antioxidant: Neogrifolin derivatives from related species (A. ovinus) demonstrate anti-oxidative activity through free radical scavenging.
• Immunosuppressive: Some grifolin derivatives have shown immunosuppressive effects, which could have implications for autoimmune disease research.

Mechanism of Action

Primary Mechanisms

1. ERK1/2 pathway inhibition and cell-cycle arrest: Grifolin inhibits the ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathway, leading to downregulation of cyclin D1 and upregulation of the cyclin-dependent kinase inhibitor p19INK4D. This results in G1 phase cell-cycle arrest, preventing cancer cell proliferation. Grifolin also inhibits ERK5 signaling, which contributes independently to cell-cycle control.

2. PI3K/AKT pathway inhibition and apoptosis: Grifolin suppresses phosphorylation of Akt and its downstream substrates, including FOXO transcription factors and GSK3. This inactivation of the PI3K/AKT survival pathway triggers mitochondria- and caspase-dependent apoptosis (increased caspase-3, -8, -9 activity; elevated Bax:Bcl-2 ratio).

3. DAPK1-mediated tumor suppression: In nasopharyngeal carcinoma cells, grifolin upregulates death-associated protein kinase 1 (DAPK1) expression via p53 activation. DAPK1 is a tumor suppressor that mediates apoptosis and has been shown to be epigenetically silenced in many cancers.

Secondary Mechanisms

• KRAS oncogene suppression: Grifolin, neogrifolin, and confluentin suppress expression of KRAS, a critical oncogene mutated in approximately 25% of all human cancers and frequently in colorectal, pancreatic, and lung cancers. Additionally, confluentin induces apoptosis and G2/M phase arrest specifically in colon cancer cells.
• Caspase cascade activation: Grifolin-induced apoptosis involves activation of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways, with caspase-3 as the downstream executioner caspase.
• Nitric oxide synthesis inhibition: Grifolin derivatives inhibit iNOS-mediated nitric oxide production in activated macrophages, providing an anti-inflammatory mechanism distinct from the antitumor activity.

Clinical Evidence Summary

No human clinical trials have been conducted with A. confluens extracts or purified grifolin/neogrifolin. All evidence is preclinical.

Preclinical Evidence (Selected)

Evidence Limitations

• All evidence is preclinical (in vitro cell culture and in vivo animal models). No human pharmacokinetic, safety, or efficacy data exist.
• Grifolin bioavailability, metabolism, and tissue distribution in humans are unknown.
• Toxicological and pharmacokinetic assessments are urgently needed before any clinical translation can be considered.
• Most antitumor studies use purified grifolin at concentrations that may not be achievable through dietary consumption of the mushroom.
• The relationship between crude mushroom extract and purified compound effects has not been systematically evaluated.
• The mushroom is not widely cultivated, limiting material availability for research and potential supplementation.

Safety Profile

General Assessment

A. confluens has been consumed as an edible mushroom in some regions, though it is not widely regarded as a choice edible due to its tough texture and sometimes acrid taste. No systematic safety evaluation has been conducted. The safety profile of grifolin and related compounds in humans is entirely unknown.

Contraindications

• Pregnancy and lactation: No safety data available. Avoid use entirely.
• Self-medication: Not recommended for self-medication for any condition. All evidence is preclinical and purified compound concentrations in studies may exceed those achievable through mushroom consumption.

Drug Interactions

• No established drug interactions. However, given grifolin’s mechanism of action involving ERK1/2 and PI3K/AKT pathway inhibition, theoretical interactions with:
  • Chemotherapy agents targeting the same pathways (MEK inhibitors, AKT inhibitors): Potential additive or synergistic effects, but clinical significance unknown.
  • Immunosuppressants: Some grifolin derivatives show immunosuppressive effects; potential additive immunosuppression is theoretical.

Side Effects

• No systematic side effect data available for A. confluens consumption or grifolin supplementation in humans.
• Gastrointestinal discomfort is theoretically possible, consistent with other polypore mushroom consumption.

Toxicology

• No formal toxicological studies have been published for grifolin, neogrifolin, or A. confluens extracts.
• Cytotoxicity data from cancer cell line studies demonstrate that grifolin affects normal cell viability at higher concentrations, suggesting a need for careful dose optimization in any future clinical applications.
• The therapeutic window between cancer cell-specific effects and general cytotoxicity has not been established.

Clinical Dosage

No Established Human Dosage

No clinical dosage recommendations can be made for A. confluens or its bioactive compounds, as no human clinical trials have been conducted.

Preclinical Reference Doses

• Grifolin in vitro: Active concentrations typically range from 10—100 micromolar in cell culture studies. IC50 values vary by cancer cell line.
• Crude extract: Research uses ethanol extracts of dried fruiting bodies. No standardized extraction protocol has been established for therapeutic use.

Research Direction

Pharmacokinetic studies determining oral bioavailability, metabolism, and tissue distribution of grifolin in animal models are needed before any dosage recommendations for humans can be developed.

Sources

• Ye M, Liu JK, Lu ZX, Zhao Y, Liu SF, Li LL, et al. Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, inhibits tumor cell growth by inducing apoptosis in vitro. FEBS Lett. 2005;579(16):3437-3443
• Luo X, Ye M, Li LL, Lu ZX, Liu SF, Fan RH, Zhao Y. Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, induces cell-cycle arrest in G1 phase via the ERK1/2 pathway. Nat Prod Res. 2008;22(6):559-565
• Luo X, Li L, Deng Q, Yu X, Yang L, Luo F, et al. Grifolin induces apoptosis via inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells. Apoptosis. 2007;12(7):1317-1326
• Luo X, Yang L, Xiao L, Xia X, Dong X, Zhong J, et al. Grifolin, a potent antitumour natural product upregulates death-associated protein kinase 1 DAPK1 via p53 in nasopharyngeal carcinoma cells. Eur J Cancer. 2011;47(2):316-325
• Yaqoob A, Li WM, Liu V, Wang C, Mackedenski S, Bhullar KS, et al. Grifolin, neogrifolin and confluentin from the terricolous polypore Albatrellus flettii suppress KRAS expression in human colon cancer cells. PLoS One. 2020;15(5):e0231948
• Jagerovic N, Hemphill CFP, Grunberg A, Gassner NC, Krummenacher D, et al. Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz.: natural fungal compounds and synthetic derivatives with in vitro anthelmintic activities and antiproliferative effects against two human cancer cell lines. Molecules. 2022;27(9):2950
• Liu XT, Winkler AL, Schwan WR, Volk TJ, Rott MA, Monte A. Grifolin derivatives from Albatrellus caeruleoporus, new inhibitors of nitric oxide production in RAW 264.7 cells. Planta Med. 2005;71(10):956-958
• Nukata M, Hashimoto T, Yamamoto I, Iwasaki N, Tanaka M, Asakawa Y. Neogrifolin derivatives possessing anti-oxidative activity from the mushroom Albatrellus ovinus. Phytochemistry. 2002;59(7):731-737
• Fan L, Pan L, Li J. The mushroom Albatrellus confluens: a minireview on phytochemistry, biosynthesis, synthesis and pharmacological activities. Curr Med Chem. 2024;31(6):732-755

Connections

• Reishi (Ganoderma lucidum): Reishi shares anticancer research interest through different mechanisms (triterpenoid-mediated NF-kB inhibition vs. grifolin’s ERK/AKT pathway targeting). Both represent polypore fungi with significant antitumor preclinical evidence.
• Turkey Tail (Trametes versicolor): Turkey Tail has the most advanced clinical evidence for mushroom-derived anticancer therapy (PSK/PSP), providing context for the earlier-stage research on grifolin from A. confluens. Both are polypore fungi producing bioactive compounds from the Russulales and Polyporales orders.
• Chaga (Inonotus obliquus): Chaga produces betulinic acid with complementary antitumor mechanisms, and like A. confluens, represents a forest polypore with promising preclinical antitumor evidence but limited clinical translation.