Properties of flavonoids in the treatment of bladder cancer (Review)

Abstract

Given its high recurrence and rapid progress, bladder cancer (BLCA) treatment has become a major problem for clinicians. BLCA is difficult to control even with surgical resection and extensive use of chemotherapeutic drugs. The non-toxicity and ease of accessibility of natural compounds have attracted much attention in recent years. Flavonoids serve an essential role given their antioxidant, antibacterial, anticancer and cardiovascular properties. They are mainly divided into several subclasses; flavones, flavanones, flavonols, flavanols, anthocyanins isoflavones and chalcones. Over the years, the role of flavonoids in BLCA has been extensively studied. The present review provided a comprehensive overview of the classification of flavonoids and substantiate the role of epithelial-mesenchymal transition, cancer stem cells, angiogenesis, epigenetic regulation and programmed cell death in BLCA. The present review emphasized that flavonoids for BLCA treatment are worthy of further study and anti-BLCA drugs have huge prospects for clinical use.

Keywords: apoptosis; bladder cancer; cell cycle; flavonoids.

Figure 1

G₁ arrest: ATM can phosphorylate CHK2 to activate the P53 pathway and the accumulation of P21 and finally cause the ubiquitination degradation of CDC25A to suppress CDK2. S and G₂ arrest: CHK1 is primarily activated by ATR, which promotes CDC25A/B/C degradation and inhibits CDK1 and cell cycle progression (18,19,187,188). ATM, Ataxia telangiectasia mutated; CHK, checkpoint kinase; CDC25, cell division cycle 25; CDK, cyclin-dependent kinase; ATR, ataxia-telangiectasia-mutated-and-Rad3-related kinase.

Figure 2

The apoptotic pathway mainly includes TNF and Fas-mediated exogenous apoptotic pathway and mitochondrial-dependent endogenous pathway. Activation of caspase-3 is the key mechanism of apoptosis. Autophagy relies on lysosomes digesting damaged proteins or organelles contained in autophagosomes. LC3 is considered to be an essential protein involved in it. GPX4 and GSH have a synergistic effect. Moreover, GPX4 can inhibit the conversion of PUFAs-OH to PUFAs-OOH, thus inhibiting lipid oxidation. GPX4, glutathione peroxidase 4; GSH, glutathione.

Figure 3

CSCs and EMT signaling pathways: After the activation of the WNT pathway, β-catenin is transported to the nucleus. During SHH signal transduction, the PTCH1 transmembrane protein receptor activates SMO and GLI 1/2 transcription factor detachment from SUFU to increase snail expression. IL-6 can activate STAT3 to modulate EMT and CSCs. P50-p65 is an important factor for NF-κB signal to exert biological function. Activation of the SMAD complex leads to enhancement of tumor progression. PI3K and PTEN antagonize each other and further regulate mTORC1/2 by phosphorylating AKT (58,189). CSCs, cancer stem cells; EMT, epithelial-mesenchymal transition; SHH, Sonic Hedgehog; PTCH1, Patched 1; PTEN, phosphatase and tensin homolog.

Figure 4

The classification of flavonoids. The main features are highlighted in red.

Figure 5

Flavones including Apigenin, Luteolin, Baicalein, Chrysin, Scutellarin, Tangeretin, Nobiletin and Orientin act on BLCA through various mechanisms such as apoptosis, cell cycle arrest and ROS activation. Apigenin is found to inhibit GSH production and promote ferroptosis. Additionally, Apigenin can inhibit UPAR, AP-1, or PI3K/AKT and NF-κB pathways to promote apoptosis, cell cycle arrest and ROS activation. Luteolin can inhibit mTOR and promote P21 expression to promote apoptosis and cell cycle arrest of BLCA cells. Tangeretin causes mitochondrial dysfunction and promotes the expression of apoptosis genes such as cytochrome C and cleaved caspase-3/9. Chrysin inhibits oncogenes such as SRC PLK1 HOXB3 and STAT3 expression. Baicalein can promote cell cycle arrest by regulating genes such as Cyclin B 1and D1. It also promotes the expression of cleaved caspase-3/9 and the occurrence of ferroptosis. Scutellarin can inhibit tumor EMT progression by inhibiting PI3K/AKT and MAPK pathways. Nobiletin has also been found to inhibit the activation of ER stress and apoptosis by inhibiting PI3K/AKT pathway. Orientin can promote apoptosis of BLCA cells by inhibiting Hedgehog and NF-KB pathways. The 2D structures of the compounds were obtained from the Pubchem database. Apigenin: PubChemIdentifier: CID 5280443 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280443#section=2D-Structure). Luteolin: PubChemIdentifier: CID 5280445 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280445#section=2D-Structure). Baicalein: PubChemIdentifier: CID 5281605 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281605#section=2D-Structure). Chrysin: PubChemIdentifier: CID 5281607 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281607#section=2D-Structure). Scutellarin: PubChemIdentifier: CID 185617 URL (https://pubchem.ncbi.nlm.nih.gov/compound/185617#section=2D-Structure). Tangeretin: PubChemIdentifier: CID 68077 URL (https://pubchem.ncbi.nlm.nih.gov/compound/68077#section=2D-Structure). Nobiletin: PubChemIdentifier: CID 72344 URL (https://pubchem.ncbi.nlm.nih.gov/compound/72344#section=2D-Structure). Orientin: PubChemIdentifier: CID 5281675 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281675#section=2D-Structure). BLCA, bladder cancer; ROS, reactive oxygen species; GSH, glutathione; EMT, epithelial-mesenchymal transition.

Figure 6

Flavonols can inhibit CSCs, angiogenesis and EMT of BLCA. In addition, they can promote BLCA apoptosis, autophagy, DNA damage, cell cycle arrest and so on. Quercetin inhibits BLCA progression by multiple mechanisms including promoting ROS, apoptosis, autophagy, cell cycle arrest nucleotides catabolism and DNA damage. Isoquercitrin can promote AMPK and inhibit STAT3, PI3K/AKT and PKC to regulate cell cycle. In addition to promoting apoptosis, Kaempferol also regulates epigenetics. Notably, silibinin can inhibit CSCs, EMT and angiogenesis. Casticin promotes DNA damage and ROS activation in BLCA cells by regulating XAF1 and TAp73. Morin can promote cell cycle arrest by inhibiting Cyclin D1, Cyclin E and CDK2/4. Icaritin is shown to promote the production of LC3II and inhibit the expression of ATG3/5/7/12 to promote autophagy. The 2D structures of the compounds were obtained from the Pubchem database. Quercetin: PubChemIdentifier: CID 5280343 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280343#section=2D-Structure). Isoquercitrin: PubChemIdentifier: CID 5280804 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280804#section=2D-Structure). Kaempferol: PubChemIdentifier: CID 5280863 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280863#section=2D-Structure). Silibinin: PubChemIdentifier: CID 31553 URL (https://pubchem.ncbi.nlm.nih.gov/compound/31553#section=2D-Structure). Casticin: PubChemIdentifier: CID 5315263 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5315263#section=2D-Structure). Morin: PubChemIdentifier: CID 5281670 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281670#section=2D-Structure). Icaritin: PubChemIdentifier: CID 5318980 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5318980#section=2D-Structure). CSCs, cancer stem cells; EMT, epithelial-mesenchymal transition; BLCA, bladder cancer; ROS, reactive oxygen species.

Figure 7

Flavanones include naringin and naringenin. They inhibit BLCA migration and promote cell cycle arrest by inhibiting MMP-2, AKT or RAS/RAF/ERK pathway. EGCG can inhibit CSCs and promote BLCA cells apoptosis and autophagy. Isoflavones including daidzein, genistein, prunetin, puerarin and formmononetin are revealed to inhibit BLCA migration and be regulated by epigenetics. Daidzein inhibits FGFR3 expression and thus promotes cell cycle arrest. Genistein is found to inhibit the PI3K/AKT and NF-KB pathways. Prunetin promotes the expression of apoptosis genes (cleaved caspase-3 and TNF-α). Puerarin inhibits BLCA growth by regulating epigenetic regulation. Formononetin inhibits miR-21 and upregulates PTEN expression to inhibit BLCA cell proliferation and promote apoptosis. The 2D structures of the compounds were obtained from the Pubchem database. Naringin: PubChemIdentifier: CID 442428 URL (https://pubchem.ncbi.nlm.nih.gov/compound/442428#section=2D-Structure). Naringenin: PubChemIdentifier: CID 932 URL (https://pubchem.ncbi.nlm.nih.gov/compound/932#section=2D-Structure). EGCG: PubChemIdentifier: CID 65064 URL (https://pubchem.ncbi.nlm.nih.gov/compound/65064#section=2D-Structure). Daidzein: PubChemIdentifier: CID 5281708 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281708#section=2D-Structure). Genistein: PubChemIdentifier: CID 5280961 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280961#section=2D-Structure). Prunetin: PubChemIdentifier: CID 5281804 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281804#section=2D-Structure). Puerarin: PubChemIdentifier: CID 5281807 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5281807#section=2D-Structure). Formononetin: PubChemIdentifier: CID 5280378 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5280378#section=2D-Structure). BLCA, bladder cancer; EGCG, epigallocatechin gallate; CSCs, cancer stem cells; miR, microRNA; PTEN, phosphatase and tensin homolog.

Figure 8

Chalcones can activate ER stress and ROS to induce BLCA cells apoptosis, ferroptosis and cell cycle arrest. Licochalcone A can promote intracellular Ca²⁺ level and activation of Calpain2, cleaved caspase-3/4/9 and Apaf-1 expression to induce cells apoptosis, ER stress and ROS. In addition, it can promote the occurrence of ferroptosis by regulating GSH. Licochalcone B is found to promote apoptosis and cell cycle arrest by inhibiting Cyclin A and CDK 1/2. Licochalcone C can inhibit the expression of the classical anti-apoptosis gene Bcl-2. Isoliquiritigenin protects the kidney by inhibiting cisplatin-induced ROS production. Flavokawain A mainly induces apoptosis of BLCA cells by promoting P27 and DR5 or inhibiting Ki67, Ha-ras, Xiap and Survivin expression. The 2D structures of the compounds were obtained from the Pubchem database. Licochalcone A: PubChemIdentifier: CID 5318998 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5318998#section=2D-Structure). Licochalcone B: PubChemIdentifier: CID 5318999 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5318999#section=2D-Structure). Licochalcone C: PubChemIdentifier: CID 9840805 URL (https://pubchem.ncbi.nlm.nih.gov/compound/9840805#section=2D-Structure). Isoliquiritigenin: PubChemIdentifier: CID 638278 URL (https://pubchem.ncbi.nlm.nih.gov/compound/638278#section=2D-Structure). Flavokawain A: PubChemIdentifier: CID 5355469 URL (https://pubchem.ncbi.nlm.nih.gov/compound/5355469#section=2D-Structure). ER, endoplasmic reticulum; ROS, reactive oxygen species; BLCA, bladder cancer; GSH, glutathione.