Table 4.

Examples of flavonoid effects on NSCLC models.

Flavonoid	Model	Effects	Ref.
Atalantraflavone	A549 and 95D cells	↓Vimentin, ↓N-cadherin ↑E-cadherin, ↓Twist1, ↓cell migration, ↓colony formation and ↑cisplatin sensitivity	[325]
Quercetin	A549 cells	↓Vimentin, ↓N-cadherin and ↓microtubular network	[277]
Quercetin-3 orutinoside	BALB/c nude mic -bearing A549 tumours	↓Akt, ↓mTOR and ↓VEGF	[326]
Hyperoside	A549 cells	↑ERK/1/2, ↓LC3-I and ↑LC3-II ↓Akt, ↓mTOR, ↓p70S6K and ↓4E-BP1	[327]
Hyperoside	A549 cells	↑AMPK, ↑HO-1, ↓survival and ↓proliferation of cells with a hypoxia phenotype	[328]
Quercetin	A549 and H460 cells	↓Akt, ↑DR 5, ↓survivin and ↑TRAIL sensitization	[329]
Quercetin	A549 cells	↓NF-κB and ↓STAT3	[330]
Quercetin	HCC827 cells	↓IL-6-induced activation of NF-kB and STAT3, ↓colony formation, ↓migration and ↓invasion
Quercetin	Mice implanted with HCC827 cells	↑E-cadherin, ↓N-cadherin and ↓tumour growth	[331]
Quercetin	1299 and H460 cells	↓NF-κB, IKKα, ↑IκBα, ↑FAS, ↑TRAILR, ↑MEKK1, ↑MEK4, ↑JNK, ↑GAD45 and ↑p21cyp	[332]
Quercetin	A549 and HCC827 cells	↑E-cadherin, ↓N-cadherin, ↓vimentin (↓Snail, ↓Slug, and ↓Twist), ↓MMP-1, ↓MMP-2, ↓MMP-7, ↓MMP-9 and ↓MMP-12	[224]
Rhamnetin	NCI-H1299 and NCI-H460 cells	↑miR-34a ↓Notch1, ↓NF-κB, ↓vimentin, ↓N-cadherin, ↓survivin, ↓cIAP1, ↓cellular migration and ↑radiosensitivity	[333]
Isorhamnetin	A549 cells	↓LC3-I and ↑LC3-II protein	[334]
Fisetin	A549 cells	↓COX-2, ↓MMP-2/9, ↑CDKN1A/B, ↑CDKN2D, ↑E-cadherin, ↓c-myc, ↓cyclin-D1 and ↓CXCR-4	[335]
Fisetin	A549 and H1299 cells	↑E-cadherin, ↓vimentin, ↓N-cadherin, (H1299), ↓ZO-1 (H1299) ↓MMP-2, stemness markers (↓CD44 and ↓CD133), ↓β-catenin, ↓NF-κB, ↓EGFR, ↓STAT3 and ↑erlotinib (a TKI) sensitivity	[236]
Fisetin	A549 cells	↓Akt, ↓mTOR, ↓p70S6K1, eIF-4E, 4E-BP1, ↓mTOR signalling molecules (↓Rictor, ↓Raptor, ↓GβL and ↓PRAS40), ↑AMPKα, ↑pTSC2, ↓p85 and ↓p110	[336]
Fisetin	HCC827 and HCC827-ER cells	↓Akt, ↓pMAPK, ↑caspase 3/8, ↑cytochrome C, ↓AXL, ↓Snail, ↑E-cadherin and ↑erlotinib sensitivity	[337]
Fisetin	A549 cells	↓NF-κB, ↓c-Fos, ↓c-Jun, ↓ERK1/2, ↓MMP-2/9, ↓u-PA, ↓adhesion, ↓invasion and ↓migration,	[338]
EGCG	A549 and H1299 sphere cells	↓β-catenin, ↓CLOCK (↓CD133, ↓CD44, Sox2, ↓Nanog, and ↓Oct4 protein) and ↓sphere formation	[81]
	Mice implanted with A549 sphere cells	↓CLOCK (↓CD133, ↓CD44, Sox2, ↓Nanog, and ↓Oct4 protein) and ↓Ki-67
EGCG	A549 and H1299 cells	↓NF-κB (↓BCL2, ↓BCL-XL, ↓COX-2, ↓TNF-α, ↓cyclinD1, ↓C-↓MYC, ↓TWIST1, and ↓MMP-2)	[322]
	Balb/c athymic nude mice implanted with resected patient tumour cells	↓NF-κB, ↓tumour volume, ↓Ki-67, ↓EMT
EGCG	HCC827-Gef cells	↓PI3Kα and ↓mTOR, ↓EMT, ↓colony formation and ↑gefitinib sensitivity	[321]
EGCG	H1299 and A549 cells	↑LKB-1, ↑AMPK (↓mTOR, ↓P70, and ↓4EBP1) and ↓cell migration	[339]
EGCG	AXL-high population of H1299 spheres	↓AXL receptor tyrosine kinase, ↓ALDH1A1 and ↓Slug	[340]
	Mice implanted with an AXL-high clone of spheres	↓p-AXL, ↓ALDH1A1, ↓Slug, and ↓tumour volume
EGCG	A549 and NCI-H460 cells	↑ROS, ↓ERK1/2, ↑CTR1 and ↑NEAT1	[341]
EGCG	A549 xenografts	↓CD31, ↓αSMA, ↓collagen IV, ↓tumour hypoxia	[342]
EGCG	Lu99 cells	↓EGF and IFN-γ-induced PD-L1 expression, ↓JAK, ↓STAT1 and ↓Akt	[323]
	A/J mice implanted with NNK-induced tumour cells	↓PD-L1, ↑IL-2 expression by tumour-specific CD3+ T lymphocytes and ↓tumour volume
EGCG	A549 cells	↑Nrf2, ↓Keap1, ↑HO-1, ↑ROS, ↑RNS, ↓Bcl-2, ↑Bax, ↑Bak, ↑Bim ↑Puma, ↓ΔΨm, and ↓EMT	[343]
EGCG	Tumour spheres (from A549, 460, and 1299 cells)	↓NEAT1, ↑CTR1 ↓CD44+ Sox2, ↓Nanog, and ↓Oct4 protein	[344]
EGCG	A549 cells	↓Nicotine-induced effects (↓HIF-1α, ↓VEGF, ↓COX-2, ↓Akt, ↓ERK1/2, ↓vimentin, and ↑E-cadherin)	[345]
EGCG	Mice implanted with A549 cells	↓HIF-1α and ↓VEGF,	[346]
EGCG	A549 cells	↓TGF-β1 induced activation of Smad2 and Smad3, ↑E-cadherin, ↓N-cadherin, ↓vimentin, ↓HAT, ↓EMT and ↓cell migration
EGCG	A549 and NCI-H460 cells	↓HIF-1α, ↓HPV-16 E6 and E7 oncoproteins, ↓VEGF, ↓IL-8, ↓Akt and ↓CD31	[347]
EGCG	Mice implanted with A549 cells	↓HIF-1α, ↓VEGF, ↓HPV-16 E6 and ↓E7 oncoproteins and ↓CD31
EGCG	A549 cells	↓IGF-1 induced expression of HIF-1α and VEGF	[348]

4E-BP1, translation repressor protein; ALDH1A1, aldehyde dehydrogenase 1; AMPK, AMP-activated protein kinase; Akt, protein kinase B; Bcl-2, B cell lymphoma 2; Bcl-xL, B cell lymphoma-extra large; CTR1, copper transporter 1; Bim, Bcl-2-interacting mediator of cell death; COX-2, cyclooxygenase-2; DR5, death receptor 5; FAS, fatty acid synthase; GADD45, cell cycle inhibition growth arrest and DNA-damage-inducible 45; cIAP1, cellular inhibitor of apoptosis protein-1; CDK1/AB, cyclin-dependent kinase inhibitor 1 A/B; CDK2D, cyclin-dependent kinase inhibitor; CLOCK, clock circadian regulator; eIF2α, eukaryotic translation initiation factor 2 subunit 1; CXCR-4, C-X-C chemokine receptor type 4; EGFR, endothelial growth factor receptor; ERK1/2, extracellular signal-regulated kinase 1/2; HIF-1α, hypoxia-inducible factor 1α; HAT, histone acetyl transferase; HO-1, haeme oxygenase 1; IκBα, inhibitor of kappa B alpha; IKKα, IκB kinase α; IFN-γ, interferon gamma; IGF-1, insulin-like growth factor-1; JAK, Janus tyrosine kinase; JNK, c-Jun NH2-terminal kinase; LC3-I/II, microtubule-associated protein 1A/1B-light chain 3 I/II; Keap1, Kelch-like ECH-associated protein 1; mTOR, mammalian target of rapamycin; MEKK1, mitogen-activated protein kinase kinase kinase 1; MMP, matrix metalloprotease; NEAT1, nuclear paraspeckle assembly transcript; 1 NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Notch 1, Notch homologue 1; Nrf2, nuclear factor erythroid 2-related factor 2; P70S6K, ribosomal protein S6 kinase beta-1; PRAS40, proline-rich Akt substrate of 40 kDa; Puma, p53 upregulated modulator of apoptosis; RNS, reactive nitrogen species; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TNF-α, tumour necrosis factor alpha; TRAILR, tumour-necrosis-factor-related apoptosis-inducing ligand receptor; TWIST1, Twist-related protein 1; uPA, urokinase plasminogen activator; VEGF, vascular endothelial growth factor; αSMA, α-smooth muscle actin; ΔΨm, mitochondrial membrane potential; ↑ = flavonoids activation/induction; ↓ = flavonoids repression/inhibition.