Abstract
Background/Aim: This review surveys scientific literature published mainly during the past five years to compile information on the anti-glioma activities of various flavonoid groups, with particular attention to structural modifications in flavonoids, isoflavonoids, and neoflavonoids.
Materials and Methods: This review is based on selective literature searches in scientific databases, mainly PubMed and Scopus.
Results: Optimal lipophilicity is probably important for flavonoid action in lipidic tissues of the brain. Many studies on flavonoids have shown that their biological activity and pharmacophore depend on the presence of three rings, one of which is heterocyclic with an oxygen atom. This ring is formed by the connection between rings A and B and is essential for the pharmacophore structure. Its shortening in iso- and neo-flavonoids results in a decreased concentration of these compounds in natural sources and possibly a decreased biological activity. Various hydroxyl groups and other substituents do not alter the basic pharmacophore structure but contribute to changes in biological activities, resulting in the inhibition of many enzymes or signaling pathways by individual flavonoids.
Conclusion: In general, because of the variation in the structure, flavonoids are capable of interacting with a high number of biological targets. As a result, a compound or compounds with high anti-glioma activity may be discovered.
Introduction
Gliomas are primary malignant neural tumors with poor prognoses, as only about 36% of patients survive five years after diagnosis (1). The limited success of current glioblastoma therapies is largely due to the aggressive invasion of malignant cells into healthy brain tissue (2). As many other factors contribute to the failure of glioblastoma therapy (3), new agents are being investigated for their ability to interfere with glioblastoma cellular processes and metabolism.
Flavonoids are naturally occurring pigments that color various flowers while protecting them from UV radiation (4). However, they can also be found in all other parts of different plants (5). They are known for possessing antibacterial and antiviral activities but do not generally display toxicity to mammal cells despite their ability to inhibit various enzymatic activities (6, 7). Flavonoids are a structurally diverse group of phenolic secondary metabolites. They can be divided into five main groups: flavonols, flavones, anthocyanidins, isoflavonoids, and neoflavonoids (5, 8). Chalcones are related to flavonoids, but their structure is less complicated (8, 9).
This review aims to summarize the accumulated knowledge on the effects of flavonoids from various structural subgroups on glioma cells and to document how minor structural modifications in these compounds influence their anti-glioma activity.
Methods
This review is based on selective literature searches in PubMed, with the word “flavonoids” always being one of the words on which any search was based. Other used terms were the names of individual flavonoids from an extensive list. Only those flavonoids for which scientific evidence of anti-glioma activity was available were included in this review. There were over 52,000 articles on this topic in PubMed in January 2025. We therefore concentrated on studies published in the last 5 years. Other public domain documents and web pages (i.e., from PubChem, Scopus,) were also consulted, PubChem being the primary source of chemical formulas used (10).
Chemical Structure of Flavonoids and Structural Differences Among Individual Subgroups
In general, flavonoids share the same structural skeleton, the flavan nucleus (Figure 1A). This is formed by two aromatic rings A and B connected by a pyran C ring. The classification of flavonoid subgroups is determined by the position at which the aromatic B ring is attached to the central C ring.
Chemical structure of flavonoids: flavan – skeleton of all main groups of flavonoids (A), flavanone (B), flavone (C), isoflavan (D), and neoflavane (E).
Arising compounds are divided into flavonoids with 2-phenylbenzopyrans scaffolds, isoflavonoids with 3-phenylbenzopyran skeleton, and neoflavonoids with 4-phenylbenzopyran skeleton (Figure 1) (11). Additionally, flavonoids with 2-phenylbenzopyran skeleton are subdivided into 3-hydroxyflavonoids (flavonols, flavanols, anthocyanidins, dihydroflavonols) (Figure 2), and flavonoids without substituent at C3 (flavanones and flavones) (Figure 1). Flavones differ from flavanones by a C2-C3 double bond (11-13). Flavones possess no hydroxyl group at position 3 while flavonols have a hydroxyl at position 3. Flavanones possess a double bond between the positions 2 and 3 of the skeleton. Additionally, flavanonols are 3-hydroxyflavanones or 2,3-dihydroflavonols, or according to IUPAC, compounds with 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one backbone (11, 13).
Chemical structure of the 3-hydroxyflavonoids flavonol (A), flavan (B), anthocyanidin, (C), and dihydroflavonol (D).
Activity of Selected Flavonoids Against Glioma Cells
Flavonoids are classified according to their structure (Figure 1 and Figure 2). Attention to different flavonoids regarding their anti-glioma activity has been uneven, with some compounds receiving considerably more scrutiny than others.
Flavanols: Flavan-3-ols: Catechins and procyanidins. Several flavonoids belong to catechins, such as 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triols (catechin and epicatechin). Gallocatechin having an extra hydroxyl group at position 5 of the phenyl ring is 2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol (Figure 3). Catechin and epicatechin differ only in the stereochemistry of the hydroxyl at the position 3 of the heterocyclic ring (Figure 3A and B). Gallocatechin possesses one extra hydroxyl at position 5′ of the aromatic phenyl B ring (Figure 3C). Gallocatechin stereochemistry at position 3 of the heterocyclic ring is the same as that of catechin, but not epicatechin (Figure 2).
Chemical structures of the flavan-3-ols catechin (A), epicatechin (B), gallocatechin (C), and epigallocatechin gallate (D).
Similarly to all other flavonoids, catechins exhibit significant antioxidative and free radical scavenging effects resulting in a string neuroprotective activity (14). Catechins are present in many plants and are abundant in blueberries, red wine, green tea, and others (14). Catechins display dose-dependent growth inhibition on human glioma cells while inducing autophagy (15) or activating the KDELR2 endoplasmic reticulum stress (ER) pathway (16). Additionally, they exhibit lower cytotoxicity in normal astrocytes. These compounds also provoke G2/M phase cell cycle arrest, impede cell migration and invasion, and block MAPK/ERK signaling (15).
It is well established that glucose metabolism is altered in glioma cells when lactate is produced even at normal oxygen levels (17). This change in glucose metabolism is reflected by the aggressiveness of glioblastoma cells (18). It was shown that the combination of temozolomide, metformin, and epigallocatechin gallate (Figure 3D) in glioblastoma may represent a therapeutic regimen that successfully reduces the progression of glioblastoma cells by normalizing glucose metabolism (18). Other metabolic pathways, i.e., epithelial-to-mesenchymal-like transition, were also studied in this respect (19).
Various catechins are capable of polymerization forming procyanidins (an example in Figure 4A) - oligomeric compounds that are the sources of cyanidins (and their cations, an example in Figure 4B) under oxidative conditions. Cyanidin as such (and its cation, Figure 4B) has five hydroxyl groups at positions 3,5,7, and 3′, and 4′. Several cyanidin 3-glycosides were described, i.e., arabinoside, galactoside, rutinoside, and rhamnoside, also in the form of their cations (10). The activity of these two groups (procyanidins and cyanidins, including their cation) has been studied scarcely.
Chemical structure of proanthocyanidin (A) (dimer of two flavan-3-ol molecules)*, cyanidin cation (B), pelargonidin cation with chloride (C). *3-hydroxyls are circled, one being free and one forming the dimer of two flavan molecules.
However, it was reported recently that procyanidin B1 may stimulate the PSMC3-NRF2 ubiquitination which leads to ferroptosis in glioblastoma cells (20). Its possible use in glioblastoma chemotherapy should be investigated in detail regarding NRF2 inhibition and slowing down glioma proliferation in vivo as the transcription factor NRF2 plays a significant role in the defense of cells against oxidative and/or toxic factors (20). At best, procyanidin B1 seems to have the potential to serve as part of an adjuvant chemotherapy regimen for patients with glioblastoma.
Cyanidin (Figure 4B) also inhibits glioma stem cell proliferation. However, it seems that the target of cyanidin is the Wnt signal transduction pathway (21). Pelargonidin differs from cyanidin by the absence of one hydroxyl group (Figure 4C). It may be present in plants as diglucoside. The effects of pelargonidin on glioma cells are similar to the effects demonstrated by cyanidin. However, the affected/studied pathway is PI3K/AKT/mTOR and pelargonidin inhibits metastasis and vascularization in vivo (22).
Flavones: Apigenin, luteolin, and tangeritin. Apigenin, luteolin, and tangeritin are representatives of flavones (Figure 5). These compounds do not have hydroxyl groups at position 3 or 4 of the heterocyclic ring. However, a double bond is present between positions 2 and 3 and ketone oxygen can be found at position 4 (Figure 5). Luteolin (Figure 5B) differs from apigenin (Figure 5A) by an extra hydroxyl at 2-phenyl substituent. Tangeritin (Figure 5C) differs from the previous compounds by having additional substituents at positions 6 and 8 of the aromatic ring A. Additionally, its 5, 6, 7, and 8 position at the aromatic ring A and position 4′ at the 2-phenyl substituent are not hydroxyls but methoxy (-O-CH3) substituents (Figure 5C). Consequently, the tangeritin molecule has no hydroxyl group.
Chemical structure of the flavones apigenin (A), luteolin (B), and tangeritin (C).
Flavone apigenin (Figure 5A) affects glioma cells significantly. Glioma cellular proliferation is suppressed in apigenin dose- and time-dependent manner (23). Furthermore, the combination of apigenin and temozolomide causes an arrest of glioma cells at the G2 phase of the cell cycle 4), and their effects on proliferation and apoptosis (23, 24), and invasiveness are also augmented by this combination of compounds. In general, these effects were achieved through interference with the PI3K/AKT pathway (23). Exposure of glioma cells to apigenin and radiation decreased the expression of lipopolysaccharide-induced NF-κB p65, GLUT-3, HIF-1α, and PKM2 proteins (25, 26). This shows that apigenin sensitizes glioma cells by depletion of cell stemness and DNA repair through inhibition of NF-κB/HIF-1α-mediated glycolysis and also by modifying expressions of several proteins (25, 26). Improved immunological profile of microglia after the treatment with apigenin was also recently documented (27).
Luteolin is structurally highly similar to apigenin from which it differs only in the presence of an extra hydroxyl group at 2-phenyl substituent (Figure 5B). Similarly to apigenin, luteolin decreased glioma cell proliferation, invasiveness, and migration. It also stimulated the apoptotic process through the expression of the related proteins [Bcl-2, caspase-3, caspase-8, and poly (ADP-ribose) polymerase (PARP)] through MAPK activation (28-31). Additionally, luteolin may induce cell-survival-promoting autophagy (29) by reducing p62 and p-Akt/Akt levels, accompanied by a pronounced accumulation of the autophagy-related LC3-II protein (31). It was also shown recently (32) that luteolin affects the sphingolipid rheostat participating in oncopromotion and limits the expression of pro-tumoral signaling, i.e., PI3K/AKT/mTOR, MAPK, RAS/MEK/ERK and cyclins regulating the progression of the cell cycle. However, luteolin upregulates proapoptotic caspase and Bcl-2 family, and cell cycle controllers, i.e., p53 and p27 (33). Furthermore, it was also documented that luteolin changes the immune microenvironment and tumor growth (34), disrupts glioblastoma cell phenotypes, and decreases the expression of pro-oncogenic genes by the glioma cells (35).
The third member of this group - tangeritin - belongs to less investigated compounds regarding its activity in glioblastoma cells. However, a derivative of tangeritin was shown to decrease viability and clonogenicity of glioma cells and to induce apoptosis by downregulating some antiapoptotic processes as it interferes with STAT3 activation by JAK2 kinase and downregulates BCL-2 (36).
Flavones: Flavonols: Quercetin, kaempferol, and fisetin. Flavonols are a subgroup of flavones with a hydroxyl group at position 3. They are polyhydroxylated with additional hydroxyl at positions 5 or 4, and/or 6 (Figure 6). Hydroxyl groups are evenly distributed around the molecule at positions 3, 5, and 7 of the bicyclic moiety, and at positions 3′, 4′, and/or 5′ of the 2-phenyl moiety. The substances that have been extensively evaluated for their anti-glioma activities are quercetin (Figure 6A), kaempferol (Figure 6B), and fisetin (Figure 6C). Other members of this group, like isorhamnetin, myricetin, pachypodol, and rhamnazin differ from the first three mentioned compounds by the presence/absence of hydroxyls and by replacement of some hydroxyls by methoxy groups. Pachypodol is the most methoxylated analog of this group with three methoxyls (Figure 6D). The anti-glioma activities of the later compounds were not studied or discussed in the scientific literature. However, it is possible that a replacement of hydroxyls (-OH) by methoxy groups (-O-CH3) makes flavonols too lipophilic for any significant biochemical activity. The limited investigation of the effects of pachypodol may be the result of its lower abundance in plant sources.
Chemical structure of the flavanols quercetin (A), kaempferol (B), fisetin (5-desoxyquercetin) (C), and pachypodol (D).
Quercetin, together with kaempferol and possibly fisetin, belongs to the most studied compounds regarding its biological activities, including anticancer and antiglioma activities. It has the highest number of hydroxyl groups out of these three compounds (Figure 6A). However, despite the numerous studies devoted to its anti-glioma activities, further investigations are necessary. A more theoretical study (37) found that quercetin may act on 96 potential targets and molecular mechanisms. Also, the synergistic action of quercetin in combination with temozolomide has been confirmed (38). This may be important for potential clinical use of quercetin. Antiglioma effects of quercetin are caused by inhibition or dysregulation of various (signaling) pathways, i.e., dual inhibition of the Wnt3a/β-Catenin pathway and the Akt/NF-κB signaling pathway (37), suppression of the Rac1/p66Shc-mediated tumor cell inflammation pathway (39, 40), decrease of the migration and invasiveness of glioma cells via suppression of the GSK-3β/β-catenin/ZEB1 signaling (41), and induction of apoptosis through suppression of the Axl/IL-6/STAT3 pathway (42).
Additionally, quercetin is capable of inducing lysosomal damage resulting in mitochondrial stress and disruption of calcium homeostasis (43) and inhibiting glycolytic metabolism (44). All quercetin effects on glioma metabolism result in changes in the concentration of various biochemical substrates and enzymes. Consequently, this molecule deserves a more intensive investigation of its many effects on glioma cells.
Additionally, it was documented that quercetin also has synergistic effects with other substances with antiglioma activities, i.e., metals, such as cadmium (45) or mercury (46).
Kaempferol is another flavonol. It differs from quercetin by the absence of one hydroxyl group at the phenyl substituent (Figure 6B). There is no reason for the lack of this hydroxyl to significantly decrease or change the biological activity of kaempferol when compared to quercetin. It is very likely that this molecule also targets numerous structures in glioma cells. It was shown that kaempferol may bind directly to epidermal growth factor receptor (EGFR) and SRC proto-oncogene and modify their phosphorylation (47) while also inhibiting EGFR/SRC/STAT3 signaling pathway in vivo (47). All these lead to the suppression of glioma cell progression and enhancement of anti-glioma activity of the drug gefitinib (47). Additionally, various kaempferol glycosides strongly bind mitogen-activated protein kinase 3 (MAPK3) related to many processes in cancerous cells, including glioma (48). When specific mechanisms of kaempferol on glioma cells were investigated, it was documented that it lowers the potential of mitochondrial membranes, induces autophagy, and consequently pyroptosis (49). The proapoptotic potential of kaempferol (50) and the mechanisms of its DNA repair inhibition (51) were well described recently.
Fisetin or 5-desoxyquercetin also belongs to this group and its anti-glioma activity has also been investigated. It differs from quercetin in the absence of only one hydroxyl at position 5 of the chromene ring. The limited studies have shown that fisetin inhibits transmembrane glycoproteins (ADAM) (52), possesses genotoxic and senolytic potential (53), and binds more strongly than quercetin with Nrf2-KEAP1 (54). Reports on the anti-glioma activity of other members of this group (isorhamnetin, myricetin, pachypodol, rhamnazin, and others) are not available.
Flavones: Flavanones: Naringenin and eriodyctiol. Flavanones are a subgroup of flavones without a double bond between positions 2 and 3 in the chromene system and a lack of a hydroxyl at position 3 (Figure 7A). The two substances with reported anti-glioma activities are naringenin (Figure 7A) and eriodyctiol (Figure 7B). Several flavonoids belong to catechins, such as 2-(3,4-dihydroxyphenyl)chroman-3,5,7-triols (catechin and epicatechin). Gallocatechin having an extra hydroxyl group at position 5 of the phenyl ring is 2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol (Figure 3). Catechin and epicatechin differ only by the stereochemistry of the hydroxyl at the position 3 of the heterocyclic ring (Figure 3A and B). Gallocatechin possesses one extra hydroxyl at position 5′ of the aromatic phenyl B ring (Figure 3C). Gallocatechin stereochemistry at position 3 of the heterocyclic ring is the same as that of catechin, but not epicatechin (Figure 2).
Chemical structure of the flavanone naringenin (A) and eriodyctiol (B), and the flavanonol taxifolin (C).
Naringenin decreased tumor invasiveness by lowering the expression of metalloproteinases (52). Effects of naringenin on glioma cells were investigated in quadruple combination with temozolomide, chloroquine, and phloroglucinol in vivo (55). It was documented that this combination induced apoptosis through modulation of the WNT/β-catenin signaling pathway leading to depolarization of the mitochondrial membrane (55, 56). Additionally, naringenin was shown to interact with tumor necrosis factor-related apoptosis-inducing ligand (APO2L) restoring its activity in glioma cells (57). This process was accompanied by the activation of caspases and by other changes in the cellular environment.
Eriodyctiol differs from naringenin by one extra hydroxyl at phenyl substituent (Figure 7B). Its anticancer activity has not been at the center of attention. However, a few scientific reports related to eriodyctiol document its ability to induce apoptosis while inhibiting proliferation and metastases. As reported for other flavonoids, eriodyctiol interferes with the PI3K/Akt/NF-κB signaling pathway (58, 59). It possesses anticancer activity in various types of tumors (in vitro and in vivo). However, the inhibition in glioma cells is the most pronounced (58), possibly due to the down-regulation of the P38 MAPK/GSK-3β/ZEB1 pathway (59).
Flavones: Flavanonols: Taxifolin. Typical structural features of flavonols are the absence of the double bond between positions 2 and 3 of the heterocyclic moiety and the presence of hydroxyl at position 3 as seen in the structure of taxifolin (Figure 7C), the only member of this group with some reports on anti-glioma activity. Dihydroquercetin and dihydrokaempferol, which are related to quercetin and kaempferol, respectively, are not mentioned in any report on anti-glioma activity.
Only one report mentioning in vitro and in vivo effects of taxifolin on glioma was found (60). Similarly to other flavonoids, taxifolin was shown to inhibit the PI3K/Akt signaling pathway in glioma. In mice, taxifolin suppressed tumor growth and activated expression of genes stimulating autophagy (60).
Anthocyanidins: Pelargonidin and cyanidin. Anthocyanidins represent an intriguing group of flavonoid aglycons as they possess a positive charge at the heterocyclic oxygen atom (Figure 2C). Some positive effects of these compounds on human health have been described, especially concerning the prevention of diseases, such as cardiovascular pathologies and neurodegeneration (61). As already mentioned, anthocyanidins form a flavylium cation with an oxonium cation at acidic pH (Figure 8) (62). As they also possess a hydroxyl at position 3 of the heterocycle, they belong to flavanols (Figure 2C).
Chemical structure of the anthocyanidins pelargonidin (A) and cyanidin (B).
There is only scarce information regarding the antiglioma activity of anthocyanidins. The available scientific literature describes only the activities of pelargonidin (Figure 8A) and cyanidin (Figure 8B). These two aglycones differ only (again) by the extra hydroxyl present in the cyanidin molecule. Pelargonidin was shown to inhibit the PI3K/AKT/mTOR pathway and to promote apoptosis (22). In vivo tests have shown an increase in the survival of experimental animals (22).
Cyanidin with an extra hydroxyl (Figure 8) was shown to affect glioma cell viability in some cell lines although the effects were not consistent across all used lines (63). Additionally, it may regulate the Wnt signaling pathway, as well as the levels of transcription factor-related products, such as Twist1 and Snail1 (63). Its glucoside interferes with the mechanism of resistance and contributes to the treatment of affected glioma cells (64).
Isoflavonoids: Isoflavones: Genistein and biochanin A. The structure of isoflavonoids is based on the skeleton of isoflavan (3-phenylchromane) (Figure 1D). Both these isoflavones are 7-hydroxyisoflavones (Figure 9) with a hydroxyl at position 7. The only difference between genistein and biochanin A is the replacement of the 4′-hydroxyl of genistein by the 4′-methoxyl in biochanin A which makes biochanin A more lipophilic than genistein.
Chemical structure of the isoflavones genistein (A) and biochanin A (B).
The anticancer properties of genistein were well summarized in (65) but with limited information regarding its anti-glioma activity. The only significant experimental study associated with the use of genistein in glioma (66) dealt with the fact that genistein can inhibit/block the DNA-PKcs/Akt2/Rac1 signaling pathway through its binding to DNA-PKcs (DNA-dependent protein kinase catalytic subunit). This results in effective inhibition of glioma cells invasiveness and migration both in vitro and in vivo (67). However, this finding was not investigated in detail or utilized in further scientific research.
Biochanin A was studied more as a sensitizer of glioma cells towards other drug therapies, especially temozolomide, where it was shown to inhibit autophagy through regulating the AMPK/ULK1 pathway (68). Initially, 63 genes were found to interact with biochanin A in glioma cells (69). These genes contribute to cell immune regulation, cell cycle inhibition, and apoptosis (69). Biochanin A was identified (68, 69) as suitable for further development of anti-glioma therapies.
Neoflavonoids. No relevant scientific information about the effects of any neoflavonoid (Figure 1E) on glioma cells was found. Table I contains information on experimental systems, cell lines, drug combinations and findings extracted from the cited publications on all flavonoids discussed in this review.
Experimental systems extracted from individual references, experimental conditions and findings.
Summary of Properties of Various Flavonoids
Flavonoids represent a significant group of biologically active compounds with many proven biological activities. They act as antibacterial agents damaging the cytoplasmic membrane, inhibiting energy metabolism and the synthesis of nucleic acids (70). They can also act as anti-inflammatory agents via inhibition of various enzymes including inflammation-reducing arachidonic acid, reduction of the expression of several molecules related to inflammation and of pro-inflammatory enzymes cyclooxygenase-2, and lipoxygenase and others (71). Flavonoids exhibit significant hepatoprotective properties (72), antiviral (73), and anti-neurodegenerative activities (74).
In this review, we aimed at summarizing data on the anti-glioma activity of various groups of flavonoids. We concentrated on the period of the last five years. Flavonoids represent an interesting group of secondary metabolites with the same skeleton and varying substitutions, mainly by hydroxyl groups or, in some cases, by methoxy groups. The minor modification of the phenoxy part of the flavonoid skeleton results in the formation of flavans, isoflavans, and neoflavans (Figure 1A, D, and E). Flavans are a subgroup of flavonoids most extensively studied for their anti-glioma activity, mainly due to their prevalence in natural sources. Interestingly, increased attention to flavonoids and their biological or potentially therapeutic activities is observed in Asian countries.
Flavonoids exist in the form of aglycons, but the attachment of various sugar moieties results in the formation of their glycosides with higher solubility compared to their aglycons, which may lead to an increase in some activities (73). However, this increase in solubility (hydrophilicity) may not be a necessary advantage for their anti-glioma activity due to lipidic nature of nervous tissue.
The flavonoids included in this review are listed in Table II. From the many biological effects, it is evident that the skeleton of flavonoids is a pharmacophore responsible for these activities. This skeleton contains 2 rings (A and B) of 6 carbons connected by a three-carbon link that is part of a six-membered heterocyclic structure containing oxygen (Figure 1A, ring C). The most important part of the flavonoid skeleton without a formed heterocycle may be expressed or abbreviated as C6-C3-C6. This type of abbreviation may be used for isoflavonoids where it would be C6-C2-C6 (Figure 1D) or for neoflavonoids, C6-C-C6 (Figure 1E). The shortening of the middle link indicates the shortening of the carbon link that is based on the shifted position of the phenoxyl substituent (ring B) on the heterocyclic part of the skeleton. The shortening of the linkage between rings A and B may be a reason behind the lower concentrations of these two groups of flavonoids in natural sources, possibly due to more complicated biosynthesis, and the less pronounced ability to interact with biochemical/biological targets. A recent review of the presence of flavonoids, isoflavonoids, and neoflavonoids indicates that as opposed to many flavonoids and a smaller number of isoflavonoids, only one neoflavonoid was discovered recently (75).
Flavonoids discussed in this review.
The various hydroxyls or other substituents do not modify this basic structure but contribute only to changes in biological activities resulting in the inhibition of many enzymes or signaling pathways by individual flavonoids. The most essential substitutions are hydroxyls at positions C3′, and also C5′ of the heterocyclic ring B. An increase in numbers of hydroxyl groups increases chelation of metal ions. This contributes to oxidative stress in glioma cells. A methoxy substituent at position C7 of the ring A also significantly contributes to neuroprotective activity. Methoxy substitutions on ring B enhance lipophilicity and penetration through cell membranes (75). The biological activities of many flavonoids are very versatile. This is illustrated by the identification of nearly one hundred targets and potential molecular mechanisms through which quercetin interacts with glioma cells (76).
The signaling pathways most often affected by flavonoids are the Akt/NF-κB signaling pathway (58, 59) and the Wnt3a/β-Catenin signaling pathway (55, 56) that may be inhibited simultaneously (76, 77), the sphingolipid rheostat pathway through (but not only) rapamycin (mTOR) signaling pathway (22, 33), the KDELR2-mediated endoplasmic reticulum stress (ER) pathway (16), the Rac1/p66Shc-mediated tumor cell inflammation pathway (39, 40), the GSK-3β/β-catenin/ZEB1 signaling pathway (41), and the Axl/IL-6/STAT3 pathway participating in apoptosis (42). Additional signaling pathways affected by flavonoids are the EGFR/SRC/STAT3 (47), DNA-PKcs/Akt2/Rac1 (67), and AMPK/ULK1 (68) signaling pathways. This variability of the involvement of flavonoids in the inhibition of so many signaling pathways indicates that this list is not complete. The ability of individual flavonoids to inhibit a specific pathway is based on the presence of the main pharmacophore – the skeleton of all flavonoids, and the various substituents.
Two important aspects of flavonoid activity that may affect outcomes in glioma cells, namely how they act in lipidic tissue and their role in therapy of multidrug resistant glioma cells, are briefly discussed further.
Flavonoid action in lipidic tissue. It is known that flavonoids achieve only low level of accumulation in lipidic tissue. However, they exhibit the same significant effects on lipid metabolism, oxidative stress, and inflammation (77, 78). Relevant representative effects of flavonoids include: 1) protection of cell membranes from oxidative damage, especially in mitochondria and adipocytes, through the prevention of lipid peroxidation (79-81); 2) inhibition of lipogenesis by downregulating fatty acid synthase and acetyl-CoA carboxylase and by stimulation of lipolysis and β-oxidation through upregulation of AMPK and PPAR-α pathways (82, 83); 3) anti-inflammatory effects in adipose tissue through modulation of adipocyte responses and improvement of metabolic homeostasis of lipidic tissue (84-86); 4) interaction with lipidic structures in the brain, such as myelin sheaths and phospholipid membranes that are essential in neuroprotection (87).
Flavonoids and their role in multidrug resistance. Multidrug resistance represents a major problem in successful treatment of glioma and other cancers because it decreases efficacy of therapeutic regimens. Multidrug resistance appears when there is overexpression of drug efflux transporters, changes in drug targets, increase of DNA repair, and decreased efficacy of apoptotic processes. The effects of flavonoids on different stages of any or all of these processes include: 1) inhibition of drug efflux transporters through the inhibition of ATP-binding cassette (ABC) transporters, i.e., P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2); 2) modulation of apoptotic pathways through improving sensitivity by upregulating pro-apoptotic proteins (e.g., Bax, caspases) or downregulating anti-apoptotic proteins (e.g., Bcl-2) or inducing mitochondrial dysfunction and oxidative stress in therapy-resistant cells; 3) interference with survival signaling pathways, i.e., PI3K/Akt, NF-κB, Nrf2/Keap1, and MAPK/ERK. This interference results in a reduction of cell proliferation and in an increase in drug sensitivity promoting apoptosis in multidrug-resistant cells; 4) synergy with other therapeutic agents; 5) contribution to epigenetic regulation, including inhibition of various histone deacetylases (HDACs).
Flavonoids hold potential in modulating drug resistance through both functional inhibition and regulation of expression. Additional clinical studies are required for the application of effective MDR-reversal strategies in oncology and other therapeutic areas (88-93).
Conclusion
In summary, the structural diversity of flavonoids makes interactions with various biological targets possible. This results in many observable biological activities. However, the increased attention of researchers to various flavonoids has not yielded a sufficient understanding of their structure-activity relationships, and predicting their efficacy in numerous pathological conditions is only partially possible. This represents a limitation for their use in therapy or the prevention of various health issues. However, the current accumulation of experimental data and the use of computational methods carry a promise for the more extensive future use of flavonoids in medicine. Combining various approaches and methods in studying the properties of flavonoids may result in the rational design and application of flavonoid-based therapeutics. At present, the flavonoids with the most promising antiglioma activities include the flavonol quercetin and the flavanones luteolin, tangeritin, and apigenin.
Acknowledgements
The Authors would like to express their gratitude to Kuwait University, Kuwait, and to St. Elisabeth University of Health and Social Work, Bratislava, Slovak Republic.
Footnotes
Authors’ Contributions
Both Authors contributed equally to this work at all stages, i.e., forming the idea for this work, gathering and analyzing the relevant information, preparing the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
Funding
The publication of this manuscript was funded by Kuwait University.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (Grammarly) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.
- Received October 13, 2025.
- Revision received November 13, 2025.
- Accepted November 27, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.