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. 2022 Sep 9;23(18):10479. doi: 10.3390/ijms231810479

Table 3.

Potential tumor preventive mechanism(s) of propolis and related flavonoids.

Mechanisms Effectiveness Based On:
Antioxidant activity Antioxidative effect of flavonoids in biological system is related to:
  • -

    ability to scavenge ROS including singlet oxygen (1 O2), hydroxyl radical (OH●), hydrogen peroxide (H2O2), superoxide anions (O2−●), perhydroxy radical (HO2●), lipid radical (LO●), and lipid peroxy radical (LOO●)

  • -

    ability to scavenge nitric reactive radical (HOONO, NO, NO3, and others)

  • -

    suppression of oxidative enzymes;

  • -

    chelation of metal ions (Fe2+, Cu2+, Zn2+ and, Mg2+)

  • -

    increased activity and protection of antioxidant enzymes

  • -

    synergistic action with other antioxidants

  • -

    inhibition of Nrf2 degradation and increase in transcriptional activity of protective genes such as antioxidant proteins and phase II detoxification enzymes
Inhibition of
nitrosation and
nitration
  • -

    flavonoids directly react with ONOO− or scavenge ·OH and ·NO2 generated by ONOO−, thus blocking the nitration reaction

  • -

    peroxynitrite scavenging and further inhibition of tyrosine nitration, DNA strand breaks, and oxidation of low-density lipoproteins
Reduction in
iron ions 		Iron reduction has multiple anticancer actions, including:
  • -

    depriving neoplastic cells of a key required nutrient,

  • -

    producing an antiangiogenic effect due to decreased ferritin

  • -

    inhibition of the formation of 8-hydroxydeoxyguanosine in vivo

  • -

    influencing cell cycle regulation at multiple sites

  • -

    tumor suppressor genes may have specific vulnerability to the iron-catalyzed Fenton reaction

  • -

    decreasing prooxidant activity of iron and other metal ions
Anti-inflammatory
effects 		Anti-inflammatory effect of flavonoids is related to:

Antioxidant activity
  • -

    radical scavenging

  • -

    inhibition of ROS production

  • -

    inhibition of prooxidative enzymes


Regulation of inflammatory cells
  • -

    modification of enzymatic activity

  • -

    adjustment of secretory processes


Regulation of proinflammatory enzymes
  • -

    suppression of arachidonic acid enzymes

  • -

    NO synthase inhibition


Modulation of proinflammatory mediators
  • -

    modulation of cytokine and chemokines production

  • -

    modulation of MMP


Modulation of pro-inflammatory gene expression
  • -

    modulation of signal transduction


Inhibition of the Toll-like receptor 4 (TLR-4) signaling pathway
Antimutagenic mechanisms Anti-mutagenic effect of flavonoids is related to:
Extracellular mechanisms
  • -

    inhibition of mutagen uptake

  • -

    inhibition of endogenous mutagens (inhibition of nitrosation; modification of the intestinal flora)

  • -

    formation of complexes with mutagens and/or their deactivation

  • -

    preferable absorption of protective compounds

Cellular mechanisms
  • -

    inhibition of or competition with mutagens (ROS scavenging; protection of DNA nucleophilic sites)

  • -

    trapping and detoxification in non-target cells

  • -

    modification of transmembrane transport

  • -

    altered function of xenobiotic metabolizing enzymes (inhibition of promutagen activation; activation of detoxification pathways)

  • -

    modulation of DNA metabolism and repair

  • -

    enhancement of apoptosis

  • -

    maintenance of genomic stability
Process of
detoxification
by fibers
  • -

    increased speed of movement of feces through colon

  • -

    dilutes carcinogens and/or slows their formation
Enzyme
inhibition 		Enzyme inhibition effect of flavonoids is related to:
  • -

    cyclooxygenase-2

  • -

    inducible nitric oxide synthase

  • -

    xanthine oxidase

  • -

    phase I enzyme (P450 enzymes, block activation of carcinogens; CYP1A1, CYP1A2, CYP1B1, CYP2E1, CYP3A4, CYP19)
Enzyme
induction and
enhanced
detoxification 		Enzymes included in this reaction are:
  • -

    sulfotransferases (SULT1A1, SULT1A3, SULT1E1)

  • -

    UDP-glucuronosyltransferases (UGT, UGT1A1)

  • -

    quinone reductase (QR)

  • -

    acetyltransferases

Effect is related to:
  • -

    inhibition of organic anion transporters participating in the uptake of nephrotoxic compounds by flavonoids and their phase II metabolites (sulfates, glucuronides)

  • -

    xenobiotic uptake and efflux by solute carrier transporters; organic anion transporting polypeptides (OATPs), organic anion and cation transporters (OATs and OCTs, respectively) and ATP-binding cassette (ABC) transporters
Inhibition of
signal transduction
pathways 		Regulate the signal transduction pathways including:
  • -

    NF-κB signaling

  • -

    PI3K/Akt/mTOR signaling

  • -

    Hedgehog signaling

  • -

    Akt, MAPKs, p53

  • -

    androgen receptor (AR), and estrogen receptor (ER) pathways

  • -

    STAT signaling

  • -

    AP-1 signaling

  • -

    Notch-1 signaling

  • -

    Wnt/β catenin signaling

  • -

    Insulin-like growth factor (IGF) signaling

  • -

    NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) pathway
Inhibition of
cell
proliferation 		Suppression of cancer stem cells self-renewal, progenitor formation, and clonal growth

Telomerase inhibition
  • -

    by decreasing levels of telomerase reverse transcriptase (hTERT) and hTR, telomerase substrates, and their associated proteins


The disruption of microtubules in mitosis
  • -

    by down-regulating tubulin in microtubules


Inhibition of topoisomerase I and II

Proteasome inhibition

Cell cycle inhibition
  • -

    by suppressing expression of cyclin A, cyclin B, Cdk2

  • -

    by enhancing the p21 and p27 levels

  • -

    by inhibiting activity of hTERT in tumor cells


Inactivation of prooxidative enzymes
  • -

    inhibiting cyclooxygenases and lipoxygenases

  • -

    decreasing xanthine oxidase


Inhibition of ornithine decarboxylase and polyamines synthesis

Modulation of signal transduction pathways
Inhibition of various protein kinases:
  • -

    protein tyrosine kinase (PTK),

  • -

    cAMP-dependent protein kinase (PKA),

  • -

    phosphoinositide 3-kinase (PI3K),

  • -

    protein kinase C (PKC),

  • -

    mitogen-activating protein kinases (MAPK),

  • -

    cyclin-dependent kinases (CDKs),

  • -

    p34cdcz kinase

  • -

    focal adhesion kinase (FAK)


Inhibition of DNA synthesis enzymes
  • -

    ribonucleotide reductase,

  • -

    DNA polymerase or topoisomerase II
Induction of cell
differentiation
  • -

    downregulation of c-Myc, inhibiting the protein kinases
Inhibition of
oncogene expression
  • -

    downregulation of c-Jun, c-Fos, c-Myc, Ki-ras
Induction of tumor
suppressor gene
expression
  • -

    modulation of p53, Rh, Bcl-2, p21, p27, BRCA1, BRCA2, RhoB
Induction of
cell-cycle arrest
  • -

    quercetin exerts growth inhibitory effect on human colon cancer via related 17 kDa protein, which blocks cell transition from G0/G1 into the S phase of the cycle

  • -

    curcumin induces cell cycle arrest in various cell types, preferentially in G2/M phase
Induction of
apoptosis 		By inhibition of heat shock proteins

Topoisomerase-mediated apoptosis
  • -

    ATP binding domain of topoisomerase II may serve as the binding site for flavonoids resulting in the inhibition of the ATPase component of the topoisomerization reaction.


Mitochondrial toxin-mediated apoptosis

Oxidative stress-induced apoptosis
  • -

    rate of autooxidation of flavonoids at pH 7.4 to form H2O2 (pyrogallol-type flavonoids generate H2O2)


Other mechanisms for inducing apoptosis
  • -

    upregulation of Bax and p21

  • -

    elevation of intracellular cAMP to high levels with cAMP analogs, adenylate cyclase activators, or phosphodiesterase inhibitors.

  • -

    increase in Ca2+ levels (endonuclease activation) and wild-type p53 overexpression.

  • -

    upregulation of TRAIL-R1 and TRAIL-R2

  • -

    downregulation of p53 and antiapoptotic proteins (Bcl2, IAP, c-FLIP, Akt)
Enhancement of
immune functions
and surveillance
  • -

    increased activity of macrophages, B, T, and NK cells

  • -

    upregulation of toll-like receptors (TLR2 and TLR4)

  • -

    inhibition of M1 to M2 macrophage polarization

  • -

    triggering Immunogenic cell death effect (ICD)

  • -

    downregulation of the PD-L1 expression through JAK-STAT and NF-κB pathways
Antiangiogenesis
  • -

    inhibition of EGF, TGFα, bFGF, VEGF, VEGFR, MMPs, claudin, β-catenin, COX2
Overcoming
resistance
to cancer therapy
  • -

    inhibition of P-gp (transcriptional downregulation of MDR-1; direct high-affinity binding to nucleotide-binding domain (NBD); ATPase inhibition; nucleotide hydrolysis; energy-dependent drug interactions with membranes enriched in transporters)

  • -

    inhibition of CYPs

  • -

    induction of apoptosis

  • -

    inhibition of NF-κB

  • -

    inhibition of glycolysis by inhibitors of glycolytic enzymes
Interaction with cellular drug transport systems
  • -

    inhibition of P-gp pump, MRP1, BCRP

  • -

    competition with glucose for transmembrane transport
Inhibition of
NF-κB 		Inhibition of NF-κB leads to negative effects:
  • -

    viability (Survivin, Bcl-2, Bcl-xL, c-FLIP, c-IAP, XIAP)

  • -

    proliferation (Cyclin D1, CDK, c-Myc, COX-2, IL-1, IL-6, TNF)

  • -

    invasion (ELAM-1, ICAM-1, MMP, urokinase-type plasminogen activator (u-PA), VCAM-1)

  • -

    angiogenesis (angiopoietin, VEGF)

  • -

    metastasis (CXCR4)
Inhibition of
cell adhesion
and invasion
  • -

    by inhibiting matrix metalloproteinase (MMP2, MMP9)

  • -

    by inhibiting intercellular adhesion molecule (ICAM; mainly ICAM-1)

  • -

    by inhibiting cysteine proteases and serine proteases such as u-PA and u-PAR

  • -

    by stimulating cell-cell communication in transformed cells, decreasing malignancy

  • -

    modulation of the platelet function

  • -

    downregulation of Rac1, CXCR4, HIF-1α

  • -

    inhibition of NF-κB and Akt signaling pathways
Inhibitors of
metastasis
  • -

    altered expression of oncogenes and tumor suppressors

  • -

    reduced migration and adhesion of cells

  • -

    reduced adhesion to laminin substrate and ability of invasion or migration

  • -

    suppression of cells migration by downregulating cell motility-related genes Rac1 and VASP

  • -

    EMMPRIN reduction via the PTEN/Akt/HIF-1α signaling pathway

  • -

    reduced cell motility due to downregulation of MMP-2 and MMP-9

  • -

    upregulation of tissue inhibitor of metalloproteinase

  • -

    inhibition of hypoxia-inducible genes involved in invasion/migration, such as uPAR, ADM, and MMP2

  • -

    decreased expression of CXCR4, through the NF-κB suppression

  • -

    inhibition of TNF-α-induced migration and EMT through Akt/NF-κB pathway inhibition

  • -

    inhibition of M1 to M2 macrophage polarization

  • -

    inhibition of EMT-inducing transcription factors (Snail, Zeba, and/or Twist)
Disruption of
tumor cell
glycolytic
metabolism
  • -

    reduction in glucose consumption and lactate production

  • -

    inhibition of expression of HIF-1 and its target genes (GLUT1, HKII, and VEGF)

  • -

    modulation of the expression of glucose transporters (especially GLUT1 and GLUT4)

  • -

    inhibition of glycolysis by inhibitors of glycolytic enzymes hexokinase 2 (HK2), phosphofructokinase (PFK), muscle isozyme pyruvate kinase M2, (PKM2), and lactate dehydrogenase A (LDHA)

  • -

    inhibition of lactate transport through monocarboxylate transporters (MCTs)
Receptor binding High concentrations could modulate receptor or enzyme activity in vivo:
  • -

    by binding to the aryl hydrocarbon receptor and reduction in dioxin toxicity

  • -

    following binding to estrogen receptor isoflavones and lignans act as phytoestrogens
Prevention of
DNA adduct
formation or
DNA intercalation
  • -

    free radicals scavenging

  • -

    protection against DNA adduct formation

  • -

    protection against chromosome aberration

  • -

    inhibition of topoisomerase enzymes (accumulation of DNA breaks and mutations without covalent binding to DNA)

  • -

    prevention of carcinogenesis by N-nitrosamines due to increased glutathione-S-transferase

  • -

    protection against H2O2-induced DNA damage by inhibiting DNA strand breaks

  • -

    protection against 8-hydroxy-2′-deoxyguanosine (8-OHdG) generation and downregulation of nuclear phospho histone H2AX expression

  • -

    protection against high glucose-induced DNA fragmentation, chromatin condensation, and hypodiploid DNA

  • -

    protection against oxidative DNA damage (intercalation into the DNA duplex and reaction with free radicals)

  • -

    helical stabilization by low flavonoid concentration

  • -

    helix opening by high flavonoid concentration

  • -

    interaction with telomerase sequences and stabilization of the G-quadruplex structure

  • -

    reactivation of p53 and DNA repair
Regulation of
steroid
hormone
metabolism
  • -

    binding to the androgen receptor (AR) and estrogen receptor

  • -

    prevention of estrogen action in promoting growth of certain tumors

  • -

    decrease in estrogen biosynthesis through aromatase inhibition
Effects on
biomarkers in
tumor promotion
  • -

    reduction in ROS, xanthine oxidase, NADPH oxidase, and peroxidase

  • -

    reduction in PKC, calcium release, and calcium canal activation

  • -

    reduction in ornithine decarboxylase, and polyamine biosynthesis

  • -

    reduction in cyclooxygenase I and II, arachidonic acid metabolism, prostaglandins, and thromboxanes

  • -

    reduction in MAPK cascades

  • -

    inhibition of AP-1 (TPA-response element) and NFκB (IκB kinase, PKC, ROS)

  • -

    downregulation of c-Jun, c-Fos, c-Myc, Bax, and Cdks (inhibiting oncogene activation)

  • -

    modulation of p53, Rh, Bcl-2, p21, p27
Prooxidative effect Prooxidative effect of flavonoids is related to:
  • -

    in the presence of O2, transition metals catalyze phenolic redox cycling and formation of reactive oxygen species (ROS) and phenoxyl radicals that can damage DNA, lipids, and other biological targets

  • -

    autoxidation of flavonols with pyrogallol or catechol B rings in the presence of transition metals increase production of ROS and accelerate oxidation of low-density lipoproteins during the propagation phase

  • -

    peroxidase-catalyzed oxidation of phenol B ring-containing flavonoids to pro-oxidant phenoxyl radicals

  • -

    peroxidase-mediated oxidation of catechol B ring-containing flavonoids results in the formation of semiquinone- and quinone-type metabolites

  • -

    prooxidant phenoxyl radicals cause mitochondrial toxicity
Antibacterial,
antiviral, and
antiparasitic activity
  • -

    reduced tumor formation related to many viruses and bacteria capable to induce inflammation and tumor including: Epstein–Barr virus (EBV), human immunodeficiency virus (HIV) infection, chronic infection with Hepatitis B (HBV) and C (HCV) virus, human T cell leukemia virus type 1 (HTLV-I)

  • -

    Helicobacter pylori (stomach cancer and MALT-lymphoma)

  • -

    Opisthorchis viverrini infection (bile duct, a rare kind of adenocarcinoma)

  • -

    Schisostoma infection—Schistosomiasis (bladder and colon)

  • -

    Herpes simplex virus type 1 and 2 infection (human cervical cancer)
The main mechanisms
of antiviral,
antibacterial, and
antiparasitic action
  • -

    inhibition of growth and adhesion to mucosal cells

  • -

    decrease in gastric concentration

  • -

    enhanced IgA response to the virus

  • -

    improvement of mucosal barrier function

  • -

    suppression of proinflammatory cytokine release
Beneficial effect
on microbiota
activity 		Direct effects of flavonoids are related to:
  • -

    positive effect on microbiota

  • -

    reduced production of deleterious endotoxins

  • -

    positive effect on the production of beneficial short-chain fatty acids (SCFA)

  • -

    systemic effect on glucose homeostasis, lipid, and energy metabolism

  • -

    prevention of the harmful effects of food, e.g., oxidants and pharmacological insults

  • -

    inhibition of hydrolytic enzymes, e.g., pancreatic lipase, amylase

  • -

    alleviation of intestinal permeabilization and associated paracellular transport of endotoxins that can initiate local/systemic inflammation

  • -

    modulation of the secretion of gut hormones by enteroendocrine cells, which have local effects and systemically modulate energy and metabolic homeostasis

  • -

    modulation of the GI tract immune system, e.g., Paneth cells (PC)

  • -

    neutralization of dietary carcinogens


Indirect effects of microbiota on cancer are related to:
  • -

    beneficial effect of microbiota on inhibition of tumor initiation

  • -

    beneficial effect of microbiota on prevention and cure of colon cancer

  • -

    beneficial effect of microbiota on immune system

  • -

    beneficial effect of microbiota in the protection of the damaged immune system after chemo- and radiotherapy

1 Certain mechanisms listed in Table 3 may be involved in several different processes.