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Flavonoids Synergistically Enhance Anti-Glioblastoma Effects of Chemotherapeutic Drugs
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Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. 

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Subjects: Oncology ; Neurosciences
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1. The Challenges of GBM Therapy and the Potential of Flavonoids

Glioblastoma (GBM) is an astrocyte-derived solid tumor of the brain or spinal cord that occurs at an overall rate of 3.19 cases per 100,000 individuals in the United States. Its incidence varies notably between subpopulations, with males and older individuals at higher risk [1]. GBM is fatal, with median survival times under one year [2].
Currently, conventional medical and surgical interventions predominate in GBM therapy. Standard treatment regimens include (1) radiation therapy with concurrent temozolomide (TMZ) chemotherapy and (2) surgical tumor resection with radiation therapy [3][4]. Recent advances in these therapies have improved patient outcomes; the addition of TMZ, an alkylating agent, to standard radiation-only regimens after 2005 greatly increased survival rates [2]. Nevertheless, conventional interventions remain constrained by GBM’s malignant properties. Surgical methods, for instance, are hindered by widespread tumor invasion and metastasis, while drug and radiation resistance—particularly associated with glioma stem cells (GSCs)—pose challenges for chemo- and radiotherapy [5][6]. Intra- and intertumoral heterogeneity further complicates anti-GBM regimens [6]. Therefore, a need exists for alternative and supportive therapies with the potential to overcome these challenges.
Dietary natural compounds constitute promising candidates in this regard; they have wide-ranging biological properties, including anti-cancer effects [7][8][9][10][11]. Among these compounds, flavonoids—polyphenolic plant secondary metabolites—are of interest. Flavonoids exert anti-cancer effects through chemosensitization, metabolic modulation, metastatic inhibition, and apoptotic induction [12][13]. Based on these well-evidenced oncostatic activities, flavonoids have great potential in modulating GBM cell responses to anti-cancer drugs by overcoming their therapeutic resistance. 

2. Flavonoids and Chemotherapeutics in GBM Therapy

2.1. Flavonoids

Bioactive flavonoids occur in fruits, vegetables, and other natural plant products and are unified by a three-ring structural backbone that includes two phenyl rings and one central heterocyclic ring. These compounds are classified based on structural differences—related primarily to the presence and positioning of substituents on the heterocycle (Figure 1). A variety of flavonoids, including flavan-3-ols, flavones, isoflavones, flavonols, flavonol glycosides, and flavonolignans, demonstrate anti-GBM effects combined with chemotherapeutic drugs in vitro and/or in vivo (Table 1).
Figure 1. General structures of flavonoids (black), flavones (blue), flavonols (red), and flavan-3-ols (green).
Table 1. Classes and sources of eight flavonoids that synergize with chemotherapeutics to inhibit GBM.
Flavonoid Class Canonical or Common Source Reference
EGCG Flavan-3-ol Green and white tea [14]
Chrysin Flavone Passionflower (Passiflora) [15]
Hispidulin Flavone Gumweed (Grindelia argentina) [16]
Formononetin Isoflavone Red clover (Trifolium pratense) [17]
Quercetin Flavonol Oak (Quercus) [18]
Icariin Flavonol Glycoside Horny goat weed (Epimedium) [19]
Rutin Flavonol Glycoside Rue (Ruta graveolens) [20]
Silibinin Flavonolignan Milk thistle (Silybum marianum) [21]

2.2. Chemotherapeutics

Conventional chemotherapeutics leverage diverse mechanistic pathways to exert their anti-cancer effects. TMZ, the canonical anti-GBM drug, is an alkylating agent that induces apoptotic cell death through the p53-dependent and O6-methylguanine-based activation of the Fas/caspase 8 pathway (Figure 2) [22]. In addition, several noncanonical and repurposed drugs hold promise in synergistic GBM therapy (Table 2).
Figure 2. Chemical structure of TMZ, an alkylating agent and anti-GBM chemotherapeutic.
Table 2. Classes and functions of chemotherapeutic drugs that have synergistic anti-GBM potential in combination with flavonoids.
Chemotherapeutic Class Primary Function Reference
ATO Arsenic compounds Multimodal [23]
Chloroquine Anti-malarials Autophagy inhibitor [24]
Cisplatin Platinum compounds Alkylating agent [25]
Etoposide Natural product derivatives Topoisomerase II inhibitor [26]
Sodium Butyrate (NaB) Short-chain fatty acids Histone deacetylase inhibitor [27]
TMZ Purine analogs Alkylating agent [22]

3. Mechanisms of GBM and Synergistic Flavonoid-Chemotherapeutic Effects

3.1. Mechanisms of GBM

GBM tumorigenesis, progression, and metastasis are driven by numerous interconnected signaling mechanisms (Figure 3). Rapid cell proliferation, an essential process at all stages of GBM development, is mediated by the Akt/mammalian target of rapamycin (mTOR), nuclear factor κappa of activated B cells (NF-κB), and other similar pathways. Uncontrolled proliferation of this nature is enabled by the inhibition of normal cell cycle controls (such as FOXO and p53), and the downregulation of key actors in autophagic (LC3, Beclin-1, and P62) and apoptotic (caspases) cell death. Moreover, a metabolic transition to aerobic glycolysis (the Warburg effect) energetically sustains rapid GBM cell division. Angiogenic and neovascular processes—stimulated mainly by vascular endothelial growth factor (VEGF) signaling—ensure oxygen and nutrient transport to growing tumors. GBM cells may further develop chemoresistance; this often occurs through O6-methylguanine methyltransferase (MGMT), which confers resistance to alkylating agents and/or P-glycoprotein (P-gp), which enhances drug efflux from the cells. Finally, Snail, Slug, and matrix metalloproteinases (MMPs) contribute to the epithelial–mesenchymal transition (EMT), which causes GBM cells to develop migratory and invasive phenotypes.
Figure 3. Multiple intracellular processes contribute to GBM tumorigenesis and progression. Mechanisms contributing to proliferation, chemoresistance, metabolism, angiogenesis, and motility (migration) are upregulated in GBM cells, while cell cycle checkpoints, autophagy, and apoptosis are inhibited.

3.2. Flavonoids and TMZ

Several flavonoids—EGCG, formononetin, hispidulin, icariin, and rutin—synergize with TMZ in modulating intracellular pathways related to proliferation, apoptosis, autophagy, migration, and chemoresistance (Figure 4Table 3).
Figure 4. The flavonoids EGCG, formononetin, hispidulin, icariin, and rutin exert pleiotropic anti-GBM effects combined with TMZ. Formononetin, hispidulin, and icariin synergistically enhance TMZ-mediated apoptosis by increasing the Bax/Bcl-2 ratio and activating caspases; formononetin additionally potentiates TMZ’s anti-migratory effects. Moreover, EGCG downregulates P-gp, thereby increasing the sensitivity of (otherwise resistant) GBM cells to TMZ. Finally, rutin inhibits TMZ-induced autophagy and, as such, promotes apoptotic cell death.
Table 3. Mechanistic anti-GBM effects of flavonoid-TMZ combinations, as demonstrated in vitro and in vivo.
Effect Cell Line Flavonoid Flavonoid Conc. TMZ Conc. Source
Increases survival time Intracranial U87 xenografts, nude mice EGCG 50 mg/kg 5 mg/kg [28]
  Intracranial U251 xenografts, nude mice EGCG 50 mg/kg 5 mg/kg [28]
Decreases tumor volume Subcutaneous U87 xenografts, BALB/c mice Rutin 20 mg/kg 55 mg/kg [29]
Decreases tumor weight Subcutaneous U87 xenografts, BALB/c mice Rutin 20 mg/kg 55 mg/kg [29]
  Intracranial U87 xenografts, BALB/c mice Rutin 20 mg/kg 55 mg/kg [29]
Increases cell death/dec viability C6 Marcela Extract 10, 20, 50 µg/mL 200 µM [30]
  U87 Marcela Extract 10, 20, 50 µg/mL 200 µM [30]
  U251 Marcela Extract 50 µg/mL 100 µM [30]
  U87MG Rutin 50, 100, 200 µM 63, 250, 500, 1000 µM [29]
  D54MG Rutin 50, 100, 200 µM 63, 125, 250, 500, 1000 µM [29]
  U251MG Rutin 50, 100, 200 µM 63, 125, 250, 500, 1000 µM [29]
  LN229 Silibinin 50 µM 10, 25, 50 µM [31]
  TR-LN229 Silibinin 50 µM 10, 25, 50 µM [31]
  U87 Silibinin 50 µM 25, 50 µM [31]
  U87MG Icariin 10 µM 200 µM [32]
  SHG44 Hispidulin 40 µM 100 µM [33]
  U87 GSLC EGCG 100 µM 100 µM [34]
  U251 EGCG 10, 20 µM 20, 40 µM [28]
  C6 Formononetin 40, 80, 160, 320 µM 125, 250, 500, 1000, 2000 µM [35][36]
  GBM8901 PWE 50 µg/mL 100, 150, 200 µM [37]
Decreases colony formation U87 Marcela Extract 10, 20, 50 µg/mL 50 µM [30]
Decreases proliferation U87MG Icariin 10 µM 200 µM [32]
Increases apoptosis U87MG Icariin 10 µM 200 µM [32]
  SHG44 Hispidulin 40 µM 100 µM [33]
  U251 EGCG 20 µM 100 µM [28]
  C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Upregulates (c-)caspase 3 (protein) C6 Marcela Extract 50 µg/mL 200 µM [30]
  U251 Marcela Extract 50 µg/mL 100 µM [30]
  U87 Rutin 100, 200 µM 500 µM [29]
  U87MG Icariin 10 µM 200 µM [32]
  C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Upregulates (c-)caspase 9 (protein) C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Upregulates (c-)PARP (protein) U87MG Icariin 10 µM 200 µM [32]
Upregulates Bax (protein) C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Downregulates Bcl-2 (protein) SHG44 Hispidulin 40 µM 100 µM [33]
  C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Downregulates Survivin (protein) LN229 Silibinin 50 µM 50 µM [31]
Downregulates LC3-II (protein) U87 Rutin 100, 200 µM 500 µM [29]
  GBM8901 PWE 50 µg/mL 100 µM [37]
Downregulates Beclin-1 (protein) GBM8901 PWE 50 µg/mL 100 µM [37]
Downregulates P62 (protein) GBM8901 PWE 50 µg/mL 100 µM [37]
Downregulates (p-)JNK (protein) U87 Rutin 100, 200 µM 500 µM [29]
Upregulates CHOP (protein) Intracranial U87 xenografts, nude mice EGCG 50 mg/kg 5 mg/kg [28]
  Intracranial U251 xenografts, nude mice EGCG 50 mg/kg 5 mg/kg [28]
Downregulates GRP78 (protein) Intracranial U87 xenografts, nude mice EGCG 50 mg/kg 5 mg/kg [28]
  Intracranial U251 xenografts, nude mice EGCG 50 mg/kg 5 mg/kg [28]
Upregulates (p-)AMPK (protein) SHG44 Hispidulin 40 µM 100 µM [33]
Downregulates (p-)mTOR (protein) SHG44 Hispidulin 40 µM 100 µM [33]
Decreases cell migration U87MG Icariin 10 µM 200 µM [32]
  C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Downregulates MMP-2 (protein) C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Downregulates MMP-9 (protein) C6 Formononetin 40, 80 µM 125, 500 µM [35][36]
Decreases cell invasion U87MG Icariin 10 µM 200 µM [32]
Increases G2/M phase arrest SHG44 Hispidulin 40 µM 100 µM [33]
Downregulates NF-κB U87MG Icariin 10 µM 200 µM [32]
Downregulates P-gp U87 GSLC EGCG 100 µM 100 µM [34]

 

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    Zhai, K. Flavonoids Synergistically Enhance Anti-Glioblastoma Effects of Chemotherapeutic Drugs. Encyclopedia. Available online: https://encyclopedia.pub/entry/17166 (accessed on 03 October 2022).
    Zhai K. Flavonoids Synergistically Enhance Anti-Glioblastoma Effects of Chemotherapeutic Drugs. Encyclopedia. Available at: https://encyclopedia.pub/entry/17166. Accessed October 03, 2022.
    Zhai, Kevin. "Flavonoids Synergistically Enhance Anti-Glioblastoma Effects of Chemotherapeutic Drugs," Encyclopedia, https://encyclopedia.pub/entry/17166 (accessed October 03, 2022).
    Zhai, K. (2021, December 15). Flavonoids Synergistically Enhance Anti-Glioblastoma Effects of Chemotherapeutic Drugs. In Encyclopedia. https://encyclopedia.pub/entry/17166
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