Flavonoids are natural substances with variable phenolic structures occurring in different fruits and vegetables (Ullah et al. 2020). Based on chemical structures, degree of unsaturation, and substitution pattern, flavonoids are classified into seven groups, namely: isoflavonoids, chalcones, anthocyanidins, flavones, flavonols, flavanones, and flavanols (Liskova et al. 2021). Recent evidence documents that flavonoids exert extensive profitable bioactive benefits on human health, including antibacterial (Yuan et al. 2021), antiviral (Ninfali et al. 2020), or anti-inflammatory effects (Choyet al. 2019; Kubatka et al. 2021). In addition, flavonoids modulate essential signaling pathways contributing to carcinogenesis and effectively suppress cancer proliferation (Zhang et al. 2018), angiogenesis (Liskova et al. 2020b), metastasis/invasion (Liskova et al. 2020a), induce apoptosis (Abotaleb et al. 2018), or sensitize cancer cells to anticancer therapy (Liskova et al. 2021). Furthermore, several studies identified the immunomodulatory properties of secondary metabolites of plants regulating innate and adaptive immunity, resulting in suppressing tumor growth and proliferation (Samec et al. 2020). Flavonoids exert an anticancer activity through the modulation of the epigenetic machinery (Fatima et al. 2021). Notably, specific carcinogenic molecular pathways associated with microRNA expression (Samec et al. 2019b), histone modifications (Samec et al. 2019a), and DNA methylation (Jasek et al. 2019) can be modulated by flavonoids. Metabolic reprogramming of cancer cells refers to the ability to alter their metabolism due to the higher energetic and nutrient demand of proliferating cells. Current evidence proved the significant anticancer activity of flavonoids through the modulation of the Warburg effect (switch from OXPHOS to aerobic glycolysis) by regulating enzymes orchestrating glucose degradation cascade (i.e., HK2, PFKM2, ENO1) or specific transporters (i.e., GLUTs and MCT1) (Samec et al. 2020). Among others, phenolic compounds regulate HIF-1 and hypoxia response that is directly associated with the modulation of aerobic glycolysis (Samec et al. 2021). In the subsequent chapters, we will discuss the role of flavonoids targeting altered metabolism in cancer via the regulation of critical cascades connected to lipid metabolism, maintenance redox balance, and utilization of amino acids, and other components to fuels cancer growth and proliferation.
3.1 Flavonoids targeting lipid metabolism
As was aforementioned, tumor cells harness altered lipid metabolism to obtain higher amounts of energy and building blocks due to increased proliferative activity (Bian et al. 2020). FAS, catalyzing the synthesis of fatty acids, plays an essential role in lipid metabolism. Luteolin (3,4,5,7-tetrahydroxy flavone), belonging to the group of flavonoids, widely found in many types of plants (Imran et al. 2019). Several studies showed the anti-lipogenic effect of luteolin in the modulation of glycolipid metabolism disorders such as diabetes, obesity, or insulin resistance (Wang et al. 2021; Kwon et al. 2015; Zang et al. 2016). Luteolin (3′,4′,5,7-tetrahydroxyflavone) also inhibited lipogenesis in prostate LNCaP and breast MDA-MB-231 cancer cell lines by suppressing FAS activity. The parallelism between attenuation of fatty acid synthesis and inhibition of cancer cell growth and increased apoptosis induction has also been documented. Notably, luteolin-mediated FAS inhibition did not affect the viability of non-cancerous cells (i.e., fibroblasts) (Brusselmans et al. 2005). Also, luteolin suppressed fatty acids palmitate synthesis by FAS inhibition in the pancreatic MIA PaCa-2 cancer cell line (Harris et al. 2012). In another study, luteolin decreased proliferation and induced apoptosis in the human choriocarcinoma model in vitro by inhibiting the PI3K/AKT/mTOR/SREBP signaling cascade, attenuating the expression of lipogenic genes (Lim et al. 2016). Like the previous study, flavonoids extracted from Canavium album Raeuseh and Citrus reticulata Blanco repressed higher FAS activity in lung A549 cancer cells. Among others, analyzed flavonoid extracts were more efficient in FAS inhibition than universal FAS inhibitor C75 (Chen et al. 2009). Interestingly, biflavonoid amentoflavone demonstrated anticancer potency via effective suppression of FAS in breast HER2 + SKRB3 cancer cells, decreasing cell viability and inducing apoptosis (Lee et al. 2013).
The crosslink between flavonoids and epigenetic mechanisms targeting lipid metabolism was observed by Su et al.. They showed that citrus peel flavonoid extracts and the mixture of their primary flavonoid compounds (tangeretin, hesperidin, and nobitelin) effectively suppressed intracellular lipid accumulation in oleic acid-treated hepatocellular HepG2 cancer cells. Treatment by both extracts changed miR-33 and miR-122 expression, resulting in the altered expression of their target genes (FAS and CPT1α) (Su et al. 2019). Several flavonoids demonstrated anticancer efficacy by modulation of SREBP transcription activity. Silibinin, isolated from Silybum marianum, inhibited aberrantly altered lipid metabolism associated with increased proliferation of prostate cancer cells through the decreased SREBP1/2 nuclear protein level and subsequent inhibition of FAS and ACLY expression. Mechanistically, a decrease in SREBP1/2 activity was mediated by AMPK activation due to the silibinin treatment (Nambiar et al. 2014).
Similarly, silibinin suppressed the progression of endometrial carcinoma cells and xenograft experiments. Treatment with silibinin inhibited proliferation, increased apoptosis, and induced cell cycle arrest in vivo and in vitro. Furthermore, silibinin inhibited the expression of SREBP1 and lipid accumulation in endometrial cancer cells (Shi et al. 2019).
Quercetin, the most abundant flavonol found in many dietary vegetables or fruits, exerts anti-inflammatory, antioxidant, cardioprotective, and anti-obesity effects (Ulusoy et al. 2020). Moreover, anti-lipogenic properties of quercetin were documented in glioma C6 cells in which quercetin significantly reduced the expression of fatty acid synthesis (via inhibition ACC1 activity) and cholesterol synthesis (via inhibition of HMGCR activity). On the contrary, quercetin treatment resulted in no effect on FAS activity. Interestingly, deeper molecular analysis revealed the regulatory effect of quercetin against altered lipid metabolism through the inhibition of SREBP 1/2 expression; thus, quercetin suppressed the main regulator of de novo cholesterol and fatty acid synthesis. Additionally, quercetin reduced the expression of carbohydrate response element-binding protein (chREBP) associated with regulation de novo lipogenesis (Damiano et al. 2019).
Genistein (7-hydroxyisoflavone), widely distributed in soybeans and soy products, has exerted anticancer activity in many experimental studies by suppressing different molecular mechanisms associated with carcinogenesis (de la Parra et al. 2016; Chen et al. 2015; Majid et al. 2010; Wei et al. 2017; Liu et al. 2016). Recent evidence suggests that genistein supports the inhibition of carcinogenesis via the modulation of various metabolic pathways leading to subsequent apoptosis of cancer cells (Tuli et al. 2019). The modulatory effect of genistein on lipid metabolism was observed also in ovariectomized rats documenting the significant role of flavonoids on metabolic changes in vivo (Nogowski et al. 1998). Genistein inhibited carcinogenesis in pancreatic Panc-1 cancer cells by attenuating gene expression of EGF-R, AKT2, NELL2, CYP1B1, Rad, and DNA ligase III. The metabolic reprogramming activities of genistein were explained by inhibiting SCD expression (Bai et al. 2004). Many studies investigated the regulatory role of HIF-1 participating in metabolic reprogramming (Samec et al. 2021; Courtnay et al. 2015; Dabral et al. 2019). Guo et al. (2021) described that increased HIF-1 protein level resulted in the upregulation of genes contributing to lipogeneses such as adipose differentiation-related protein (ADRP), FAS, and SREBP1 in NSCLC cells. Moreover, hypoxic conditions interrupted paclitaxel-induced cell cycle arrest.
Moreover, treatment with FV-429 (derivative of flavonoid wogonin) combined with paclitaxel reprogrammed HIF-1 modulated fatty acid metabolism in NSCLC and enhanced sensitivity of NSCLC cells to paclitaxel. Furthermore, FV-429 enhanced the chemosensitivity of the tumor to paclitaxel in vivo by suppressing its lipid metabolism (Guo et al. 2021). Similarly, oroxylin A, isolated from Scutellariae radix, reprogrammed cancer fatty acid metabolism by modulating HIF-1 and subsequently decreasing the intracellular fatty acid level and accelerating fatty acids oxidation, inhibiting colorectal cancer cell growth and proliferation (Ni et al. 2017).
As described above, AMPK acts as a significant energy balance sensor and reduces tumor growth and proliferation by inhibiting de novo lipogenesis. Morusin is a prenylated flavonoid obtained from Morus alba with antioxidant and anti-inflammatory properties (Panek-Krzyśko and Stompor-Gorący 2021). In vitro analysis detected, among others, the anticancer effect of morusin demonstrated via activation of AMPK in hepatocellular Hep3B and Huh7 cancer cell lines (Cho et al. 2021). Another flavonoid, isoangustone-A, induced cell death in colorectal SW480 cancer cells and inhibited tumor growth in xenografts bearing SW480 cells by activating AMPK signaling (Tang et al. 2021). Last but not least, epigallocatechin-3-gallate (EGCG) nanoemulsion exhibited antiproliferative, anti-invasive, and anti-migratory activities in lung H1299 cancer cell line through the activation of activation AMPK signaling (Chen et al. 2020).
Due to the significant role of AMPK in the modulation of lipid metabolism through the inactivation of its downstream target ACC (Li et al. 2015), there is an imminent need for further investigation in the area of flavonoids affecting AMPK during cancer development. Table 2 and Fig. 1summarize an overview of flavonoids targeting specific components of lipid metabolism.
Table 2
Flavonoids targeting lipid metabolism in preclinical research
Flavonoid
|
Study design
|
Effects
|
Mechanism
|
References
|
Luteolin
|
LNCaP prostate cancer cells; MDA-MB-231 breast cancer cells
|
↓ lipogenesis
↓growth
↑ apoptosis
|
↓ enzymatic activity of FAS
|
(Brusselmans et al. 2005)
|
MIA PaCa-2 pancreatic cells
|
↓ proliferation
|
↓ fatty acid palmitate synthesis via modulation of FAS activity
|
(Harris et
al. 2012)
|
JAR and JEG-3 choriocarcinoma cell cells
|
↑ apoptosis
↓ proliferation
↓ viability
|
↓ activities of PI3K/AKT, ERK1/2, and mTOR pathways;
↓ SREBP1/2 mRNA expression but only SREBP1 protein expression was affected by luteolin treatment
|
(Lim et al. 2016)
|
Flavonoids extracts from Canavium album Raeuseh and Citrus reticulata Blanco
|
A549 lung cancer cells
|
↓ proliferation
|
↓ Enzymatic activity of FAS
|
(Chen et
al. 2009)
|
Amentoflavone
|
HER2-positive SKBR3 breast cancer cells
|
↓ cell viability
↑ apoptosis
|
↓ FAS mRNA expression through the suppression of SREBP1 translocation in cancer cells
|
(Lee et al. 2013)
|
Citrus peel flavonoid extracts/tangeretin, hesperidin, and nobitelin mixture
|
HepG2 human hepatoma cells
|
↓lipid accumulation
|
↓ miR-33 and miR-122 affected the expression of FAS and CPT-1α, leading to inhibition of lipid accumulation
|
(Su et al. 2019)
|
Silibinin
|
LNCaP, DU145, and PC3 prostate cancer cells
|
↓ proliferation
↓lipid accumulation
|
↑ AMPK activity mediated by silibinin leads to inhibition of SREBP1 nuclear translocation due to its increased phosphorylation
|
(Nambiar et
al. 2014)
|
Ishikawa and RL-952 endometrial cancer cells
|
↑ apoptosis
→ cell cycle arrest
↓ proliferation
↓lipid accumulation
|
↓ expression of SREBP1 and its downstream genes associated with lipid metabolism, including SCAP, FAS, ACLY HMGCR, and SCD-1
|
(Shi et al. 2019)
|
Quercetin
|
Rat C6 glioma cells
|
↓de novo cholesterol and fatty acids biosynthesis
|
↓ mRNA and protein level of ACC1 and HMGCR;
↓ expression of SREBP1/2 and chREBP directly contributing to de novo lipogenesis
|
(Damiano et
al. 2019)
|
Genistein
|
Panc-1 pancreatic cancer cells
|
↓tumor growth
↓proliferation
|
↓ expression of EGF-R, AKT2, NELL2, CYP1B1, Rad, DNA ligase III, and SCD;
↓ level of 18s and 28s rRNA;
↑ expression of EGR-1 and IL-8
|
(Bai et al. 2004)
|
FV-429
|
A549 and NCI-H460 NSCLC cells; Balb/c nude mice
|
↑ sensitivity to paclitaxel therapy
→ cell cycle arrest
|
in vitro
↓ lipid droplet accumulation;
↓overall reduction of free fatty acids;
↓ FAS, ADRP, CPT1, and SREBP1 mRNA and protein expression
in vivo
↓ HIF-1α, SREBP1, FAS, ADRP and FABP7 and ↑ CPT1 expression in the combination treatment group (paclitaxel + FV429)
|
(Guo et al.
2021)
|
Oroxylin A
|
HCT116 colorectal cancer cells; Balb/c nude mice
|
↓tumor growth
↓proliferation
→ cell cycle arrest
|
in vitro
↓ lipid droplet accumulation;
↓ ADRP, SREBP1 and FAS and ↑ CPT1 protein/mRNA expression;
↓HIF-1α protein level;
↓ Wnt signaling pathway and ↓ nuclear translocation of β-catenin.
In vivo
↓ tumor growth and delayed progress of primary colon cancer by oroxylin A administration
|
(Ni et al. 2017)
|
Explanatory notes ↓ downregulation/inhibition; → induction; ↑ upregulation/promotion Abbreviations: FAS, fatty acid synthase; PI3K/AKT, phosphoinositide 3-kinase/AKT; ERK1/2, extracellular signal‑regulated protein kinase 1/2; mTOR, mammalian target of rapamycin; SREBP1/2, sterol regulatory element-binding protein 1/2; CPT1, carnitine palmitoyltransferase 1; AMPK, AMP-activated protein kinase; SCAP, cleavage activating protein; ACLY, ATP-citrate lyase; HMGCR, hydroxyl-methyl glutaryl-coenzyme A reductase; SCD1, stearoyl-CoA desaturase; ACC1, acetyl-CoA carboxylases; chREBP, carbohydrate response element-binding protein; EGF-R, epidermal growth factor receptor; NELL2, neural EGFL Like 2; CYP1B1, cytochrome P450 Family 1 Subfamily B Member 1; EGR-1, early growth response protein 1; IL-8, interleukin-8; ADRP, adipose differentiation-related protein; FABP7, fatty acid-binding protein 7; HIF-1α, hypoxia-inducible factor 1α
|
3.2 Flavonoids and redox balance mediated by Nrf2
It is well known that Nrf2 prevents oncogenesis in healthy cells by expressing genes responsible for the antioxidant response. Stabilized Nrf2 is translocated into the nucleus and subsequently heterodimerized with small Maf proteins (sMafs). This complex binds to the DNA region known as the antioxidant response element (ARE), resulting in the expression of detoxification enzymes. On the other hand, persistently activated Nrf2 protects malignant cells against chemotherapy and radiotherapy (Zimta et al. 2019). Several studies identified the role of flavonoids in regulating Nrf2 and its downstream targets, leading to the suppression of cancer progression.
Apigenin (4′,5,7-trihydroxyflavone), widely found in many vegetables and fruits, exerts numerous beneficial properties, including antioxidant and anticancer activities (Yan et al. 2017). As was noted, Nrf-2-induced pathways associated with metabolic control of the redox state have essential roles in the development of chemo and radioresistance of cancer cells. Apigenin sensitized doxorubicin-resistant hepatoma BEL-7402 cancer cell line to anthracycline doxorubicin. Apigenin increased the sensitivity of cancer cells to the chemotherapeutic agents via reduction of Nrf2 expression at both mRNA and protein levels. A deeper analysis revealed that apigenin affected the PI3K/Akt signaling pathway, which subsequently reduced the expression of Nrf2 downstream gene targets. In vivo experiments demonstrated the role of apigenin combined with doxorubicin in inhibiting tumor growth, proliferation, and induction of apoptosis (Gao et al. 2013a). In another study, Gao et al. (2017) identified the anticancer role of apigenin via inhibiting the miR-101/Nrf2 pathway in doxorubicin-resistant BEL-7402 cells. Apigenin reversed resistance to doxorubicin and induced apoptosis in hepatocellular cancer cells. Epigenetically, apigenin induced miR-101 expression and subsequent downregulation of Nrf2, leading to increased sensitivity of doxorubicin-resistant BEL-7402 to doxorubicin-mediated chemotherapy (Gao et al. 2017). The promising cancer-inhibitory effects of the flavonoid luteolin was demonstrated in mice bearing NSCLC A549 cells. Luteolin effectively inhibited the Nrf2 signaling pathway that suppressed tumor growth in vivo. Additionally, luteolin reduced the protein level of antioxidant enzymes (contributing to intracellular redox state) regulated by Nrf2, including NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), aldo-keto reductase 1C (AKR1C), and glutathione S-transferase Mu 1 (GSTm1). Notably, luteolin decreased glutathione levels and enhanced the therapeutic effect of cisplatin (Chian et al. 2014). Furthermore, luteolin reduced cell viability and induced apoptosis in cholangiocarcinoma KKU-100 cell line. Acquired data showed that luteolin increased reactive oxygen species (ROS) production and induced glutathione depletion in KUU-100 cells. Mechanistically, luteolin significantly reduced Nrf2 expression and the expression of its downstream genes. Among others, luteolin enhanced apoptosis by releasing cytochrome C and reduced Bcl-2 and Bcl-XL protein levels (Kittiratphatthana et al. 2016).
Like apigenin, chrysin 5,7-dihydroxyflavone re-sensitized doxorubicin-resistant BEL-7402 to doxorubicin through the downregulation Nrf2 at both mRNA and protein levels. From the molecular point of view, the Nrf2 pathway inhibition was mediated by the downregulation of PI3K-Akt and ERK pathways (Gao et al. 2013b). Also, chrysin and nanostructured lipid carriers (NLCs), were used to increase doxorubicin's cytotoxic effect in breast MCF-7 cancer cells. Chrysin-loaded NLCs significantly decreased mRNA expression of Nrf2, NQO1, multidrug resistance-associated protein 1 (MRP1), and HO-1 (Sabzichi et al. 2017).
The decreased expression of Nrf2 and its downstream genes associated with redox balance was documented in breast cancer MCF-7, MDA-MB 231, and MDA-MB 468 cell lines after using quercetin with vitamin C (Mostafavi-Pour et al. 2017). Additionally, the synergic effect of quercetin and vitamin C significantly reduced the expression of Nrf2 at both mRNA and protein levels, along with the activity of crucial enzymes contributing to the regulation of oxidative stress such as glutathione peroxidase, glutathione reductase, HO-1, and NQO1 in prostate PC3 cancer cells (Abbasi et al. 2021).
As was discussed above, SLC1A5 mediating glutamine (precursor of glutathione) uptake is upregulated by Nrf2. Isoquinoline flavonoid berberine modulates redox balance by reducing glutamine uptake in Hep3B and BEL-7404 hepatocellular cancer cell lines by suppressing SLC1A5 transporters. Furthermore, berberine reduced tumor growth by inhibiting SLC1A5 expression in vivo (Zhang et al. 2019). Also, quercetin was suggested to be an inhibitor of SLC1A5 in colon cancer cells to overcome the resistance of cancer cells to chemotherapy mediated by doxorubicin (Zhou et al. 2020).
The mixture of secondary metabolites (i.e., flavonoids, polyphenols, aromatics, etc.) found in Aronia melanocarpa Elliot exerts many beneficial properties by targeting cancer cells' detoxification machinery via modulation metabolic pathways. Yu et al. analyzed the oncostatic efficacy of Aronia melanocarpa Elliot anthocyanins (AMA) against colon cancer in vivo (C57BL/6 mice model) and in vitro (Caco-2 colon cancer cell line). AMA significantly inhibited the proliferation of Caco-2 cells, suppressed cancer-related inflammation (decreased level of inflammatory cytokines), and reduced glutaminase and SLC1A5 (Yu et al. 2021). Table 3 and Fig. 2provide an overview of flavonoids that interact with upregulated Nrf2 and its downstream genes associated with redox balance in carcinogenesis.
Table 3
Flavonoids targeting the redox state in cancer cells
Flavonoid
|
Study design
|
Effects
|
Mechanism
|
References
|
Apigenin
|
BEL-7402 hepatocellular cancer cells;
BALB/c nude mice
|
↓ tumor growth
↓ proliferation
↑ apoptosis
↑ sensitivity to doxorubicin
|
↓ Nrf2 mRNA and protein expression via the downregulation of PI3K/Akt pathway
|
(Gao et
al. 2013b)
|
BEL-7402 hepatocellular cancer cells
|
↑ apoptosis
↑ sensitivity to doxorubicin
|
↑ miR-101 expression inhibiting Nrf2 expression and re-sensitizing BEL-7402 cells to doxorubicin;
↑ caspase-dependent apoptosis
|
(Gao et al. 2017)
|
Luteolin
|
C57BL/6 mice bearing A549 lung cancer cells
|
↓ xenograft tumor growth
↑ sensitivity to cisplatin
↓ proliferation
|
↓ Nrf2 expression;
↓ NQO1, AKR1C, HO-1, and GSTm1;
↑ efficacy of combined therapy (Luteolin + cisplatin) than luteolin or cisplatin therapy alone
|
(Chian et
al. 2014)
|
KKU-100 cholangiocarcinomaoma cells
|
↑ apoptosis
↓ viability
|
↑ ROS production is associated with ↓ Nrf2, γ-glutamylcysteine ligase, and HO-1 expressions;
↑ mitochondrial depolarization associated with apoptosis (releasing cytochrome c and decreasing Bcl-2 and Bcl-XL proteins);
→ activation of caspases − 3 and − 9
|
(Kittiratphatthana et al. 2016)
|
Chrysin
|
BEL-7402 hepatocellular cancer cells
|
↑ sensitivity to doxorubicin
|
↓ Nrf2 mediated by downregulation of PI3K-Akt and ERK pathways;
↓ HO-1, AKR1B10, and MRP5 (Nrf2 downstream genes) expression associated with re-sensitization of cancer cells to doxorubicin treatment
|
(Gao et
al. 2013a)
|
MCF-7 breast cancer cells
|
↑ sensitivity to doxorubicin
↑ apoptosis
|
↓ Nrf2 expression as well as decreased expression of downstream genes regulated by Nrf2 (MRP1, HO-1, NQO1);
↑ Cellular uptake of doxorubicin mediated by the synergic effect of chrysin and NLCs
|
(Sabzichi et
al. 2017)
|
Quercetin + Vitamin C
|
MCF-7, MDA-MB 231, MDA-MB 468 breast cancer cells
|
↓ proliferation
|
↓ Nrf2 mRNA and protein levels;
↓ the activity of NQO1, HO-1, glutathione peroxidase, glutathione reductase, and glutathione
|
(Mostafavi-Pour et al. 2017)
|
Quercetin + Vitamin C
|
PC3 prostate cancer cells
|
↓ viability
|
↓ Nrf2 mRNA and protein levels;
↓ the activity of NQO1, HO-1, glutathione peroxidase, glutathione reductase
|
(Abbasi et al. 2021)
|
Berberine
|
Hep3B and BEL-7404 hepatocellular cancer cells;
BALB/c nude mice
|
↓ proliferation
↓ tumor growth
|
↓ SLC1A5 expression in vitro and in vivo
|
(Zhang et al. 2019)
|
Quercetin
|
SW620/Ad300 colon cancer cells
|
↑ sensitivity to doxorubicin
|
↓ SLC1A5 expression and glutathione level
|
(Zhou et al. 2020)
|
Aronia melanocarpa Elliot anthocyanins (AMA)
|
Caco-2 colorectal cancer cells; C57BL/6 mice
|
↓ proliferation
↓cancer-related inflammation
|
↓ inflammatory cytokines (i.e., IL-17, IL, 6, TNF-α, IFN-γ, MUC2 and COX-2);
↓ level of SLC1A5 and glutaminase
|
(Yu et al. 2021)
|
Explanatory notes ↓ downregulation/inhibition; ↑ upregulation/promotion Abbreviations: Nrf2, nuclear factor-erythroid factor 2-related factor 2; PI3K/AKT, phosphoinositide 3-kinase/AKT; NQO1, NAD(P)H quinone oxidoreductase 1; AKR1C, aldo-keto reductase 1C; HO-1, heme oxygenase 1; GSTm1, glutathione S-transferase Mu 1; ROS, reactive oxygen species; Bcl-2, B-cell lymphoma-2; Bcl-XL, B-cell lymphoma-extra-large; ERK, extracellular signal‑regulated protein kinase; AKR1B10, aldo-keto reductase family 1 member B10; MRP5; multidrug resistance-associated protein 5; MRP1, multidrug resistance-associated protein 1; SLC1A5, solute-linked carrier family A1 member 5; IL-17, interleukin 17; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; MUC2, mucin-2; COX-2, cyclooxygenase-2
|
3.3 Role of flavonoids modulating utilization of alternative fuels for carcinogenesis
Many non-glucose nutrients participate in cancer cell progression as alternative fuels to fulfill increased cellular energetic and biosynthetic requirements (Keenan and Chi 2015). As was noted previously, amino acid glutamine plays a vital role in maintaining redox balance in cancer cells (Choi and Park 2018). In addition to glutamine, other amino acids, including serine, glycine, or asparagine and ketone bodies, are critical for the higher metabolic demand of tumors (Geeraerts et al. 2021). Several research teams demonstrated the effect of flavonoids on amino acid metabolism and ketone bodies utilization, but the number of experimental studies is still limited.
Quercetin affected the expression of essential genes contributing to arginine metabolism. Jamehdor et al. used human embryonic kidney cells (HEK293) to evaluate the impact of quercetin on arginine metabolism. The authors observed significant differences in the expression of genes (e.g., arginase 1/2, ornithine carbamoyltransferase, or nitric oxide synthase 1) after treatment with quercetin (Jamehdor et al. 2021).
Moreover, EGCG exhibited anticancer efficacy by inhibiting phosphoglycerate mutase 1 (PGAM1) in lymph node non-small cell lung carcinoma cell line derived from the lymph node NCI-H1299 and breast cancer MDA-MB-231 cell line. PGAM1 is critical for glycolysis, the pentose phosphate pathway (PPP), and serine biosynthesis, and its inhibition mediated by EGCG led to the suppression of cancer cell line proliferation (Fig. 3) (Li et al. 2017).
HMGCS2 directly participates in generating ketone bodies as mitochondrial fuels to promote the anabolic growth of human cancer cells (Shi et al. 2019). Upregulation of HMGCS2 has been observed in cancer-associated fibroblasts resulting in the promotion of carcinogenesis. Nobiletin, an O-methylated flavonoid extracted from citrus peel, suppressed CD-36 mediated migration, angiogenesis, and invasion by targeting the CD36/STAT3/NF-κB signaling cascade. In addition, nobiletin significantly reduced the expression of HMGCS2 in breast cancer cells (Sp et al. 2018). Furthermore, alternating consumption of quercetin and β-glucan downregulated the expression of HMGCS2 and other genes connected with colon cancer in mice and thus, reduced their mortality (Qi et al. 2019). Monocarboxylate transporters (MCTs) are membrane proteins responsible for transporting nutrients, including pyruvate, lactate, and ketone bodies (Haapasalo et al. 2021). EGCG effectively inhibited colorectal malignancy by targeting cancer-associated fibroblasts (CAFs). Further, a more in-depth investigation revealed the capabilities of EGCG to inhibit MCT4 in stromal cells and thus affect colorectal cancer progression (Fig. 4) (Chen et al. 2022). Table 4shows an overview of experimental studies focused on flavonoids targeting amino acids metabolism and ketone bodies utilization as alternative fuels associated with carcinogenesis.
Table 4
Flavonoids modulating synthesis and flux of alternative fuels (amino acid metabolism and ketone bodies) for cancer development
Flavonoid
|
Study design
|
Effects
|
Mechanism
|
References
|
EGCG
|
NCI-H1299 human non-small cell lung cancer cells; MDA-MB-231 breast cancer cells
|
↓ proliferation
↓ glycolysis
|
↓ enzymatic activity of PGAM1
|
(Li et al. 2017)
|
Nobiletin
|
MCF-7 and MDA-MB-231 breast cancer cells
|
↓ angiogenesis
↓ migration
↓invasion
↓ sphere formation
|
↓ HMGCS2 expression;
inhibiting role of nobiletin mediated by modulation of CD36/ (STAT3)/NF- κB signaling axis
|
(Sp et al. 2018)
|
Quercetin + β-glucan
|
C57BL/6J mice with colorectal cancer
|
↓ mortality
|
↑ the abundance of Parabacteroides, associated with attenuation of tumor formation;
↓ expression of cancer-associated genes HMGCS2, FABP2, and GPT
|
(Qi et al. 2019)
|
EGCG
|
HCT-116 and HT-29 colorectal carcinoma cells; human intestinal fibroblasts (HIFs)
|
↓ proliferation
↓ migration
↓ glycolytic activity
colorectal cancer malignancy
|
↓ colorectal cancer malignancy via the targeting CAFs metabolism;
↓ MCT4 activity
|
(Chen et al. 2022)
|
Explanatory notes ↓ downregulation/inhibition; ↑ upregulation/promotion Abbreviations: EGCG, epigallocatechin-3-gallate; PGAM1, phosphoglycerate mutase 1; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; STAT3, signal transducer and activator of transcription 3; CD36, cluster of differentiation 36; NF- κB, nuclear factor kappa B; FABP2, fatty acid-binding protein 2; GPT, glutamic--pyruvic transaminase; CAFs, cancer-associated fibroblasts; MCT4, monocarboxylate transporter 4
|