Table 2.

Suppression of tumor promotion by anti-inflammatory effects of flavonoids

Flavonoid	Cancer	Study design	Anti-inflammatory effects and/or mechanisms of tumor suppression	Ref
Preclinical studies
Green tea polyphenols	Skin tumor	Six-week-old female SENCAR mice	↓ Stage I and stage II skin tumor promotion, ↓ skin papilloma formation, ↓ tumor multiplicity, ↓ tumor incidence, ↓ tumor growth	[118]
Silymarin			↓ Stage I and stage II skin tumor promotion, ↓ skin papilloma formation, ↓ tumor multiplicity, ↓ tumor incidence, ↓ tumor growth	[119]
Apigenin			↓ Skin papilloma formation, ↓ incidence of carcinomas/papillomas	[120]
Quercetin	Primary effusion lymphoma	BC3, BCBL1, and BC1 primary effusion lymphoma cells	↓ PI3K/AKT/mTOR, ↓ Wnt/β-catenin, ↓ STAT3, ↓ IL-6, ↓ IL-10, ↓ c-FLIPL, ↓ cyclin D1, ↓ cMyc	[121]
Icaritin	Chronic myeloid leukemia	K562 and primary chronic myeloid leukemia cells; 6–8-week-old female NOD-SCID nude mice	↓ Proliferation, ↓ tumor growth, ↑ apoptosis, regulation of MAPK/ERK/JNK, regulation of JAK2/STAT3/AKT, ↑ p-JNK, ↑ p-C-JUN, ↓ p-ERK, ↓ p-P38, ↓ JAK-2, ↓ p-JNK, ↓ p-STAT3, ↓ p-AKT	[122]
Fisetin	Lung cancer	IL-1β-promoted inflammatory responses of A549 lung adenocarcinoma cells	↓ ICAM-1, ↓ COX-2, ↓ PGE2, ↓ IL-8, ↓ CCL5, ↓ monocyte chemotactic protein 1, ↓ TNF- α, ↓ IL-6, ↓ NF-κB, ↓ ERK1/2	[123]
	Laryngeal carcinoma	TU212 head and neck squamous cell carcinoma cells; 6–8-week-old SPF male BALB/c nude mice	↑ Apoptosis, ↑ caspase-3, regulation of PI3K/AKT/NF-κB signaling, ↓ proliferation, ↓ tumor volume and weight, ↓ KI67, ↓ ERK1/2, ↓ PI3K/AKT-regulated mTOR	[124]
Fisetin + carnosic acid	Lung cancer	HCC827 and H358 human lung cancer cell lines; 8-week-old athymic nude mice injected with HCC827 and H358 cells	↑ Anti-inflammatory effects, ↑ apoptosis, ↑ caspase-3, ↑ Bax, ↑ Bad, ↓ Bcl-2, ↓ Bcl-xl, ↑ death receptor of TRAIL	[125]
Luteolin	Glioma	U251 and LN229 glioma cells	↓ Proliferation, ↑ apoptosis, ↑ MAPK, ↑ JNK, ↑ ERK, ↑ p38, ↑ FADD, ↑ caspase-8, ↑ caspase-3, ↑ PARP, ↑ autophagy, ↑ LC3B II, ↑ LC3B I, ↓ p62	[126]
	Gastric cancer	SGC7901, SGC7901/DDP, HGC27, MGC803, BGC803, and BGC823 gastric cancer cell lines; 6-week-male nude Balb/c SGC7901, SGC7901/DDP, and HGC27 murine xenografts	↓ STAT3, ↓ Mcl-1, ↓ Survivin, ↓ Bcl-xl, disruption of the binding of HSP-90 to STAT3, ↓ tumor growth	[127]
Luteolin + apigenin	Lung cancer	H358 murine xenografts and Lewis lung carcinoma in vivo model	↓ Lung cancer cell growth, ↑ apoptosis, ↓ IFN-γ-induced PD-L1 expression, ↓ STAT3 phosphorylation	[128]
Apigenin	HCC	HepG2 HCC	↓ Cell proliferation, ↑ apoptosis, ↑ autophagy, ↓ PI3K/AKT/mTOR pathway	[129]
	Leukemia	RBL-2H3 rat leukemia cells	↓ Lyn, ↓ Syk, ↓ phospholipase Cγ1, ↓ ERK, ↓ JNK, ↓ TNF-α, ↓ IL-4, ↓ IL-5, ↓ IL-6, ↓ IL-13, ↓ COX-2	[130]
	Esophageal cancer	Eca-109 and Kyse-30 human esophageal cancer cells	↓ IL-6, ↓ cell proliferation, ↑ apoptosis, ↑ PARP, ↑ caspase-8	[131]
Bilberry extracts + isoquercitrin	HCC	PBO-promoted rats	↓ Proliferation, ↓ Ki67, ↓ microsomal ROS, ↓ p-PTEN, ↓ p-AKT, ↓ Smad4,	[132]
Scutellaria flavonoids (baicalin, baicalein, and wogonin)	Non-small-cell lung carcinoma	A549 cells and H1299 non-small cell lung carcinoma cells; murine A549 xenografts (6-week-old male Balb/c thymic nude mice)	↓ Id1, ↑ Rap1-GTP binding, dephosphorylation of AKT and Src	[134]
Baicalein and baicalin	Liver cancer	SMMC-7721 and HepG2 human liver cancer cells	↓ PD-L1 expression, ↓ IFN-γ, ↓ STAT3 activity	[135]
Sugarcane	Colon cancer	SW480 colon cancer cells	↓ NF-κB phosphorylation, ↓ IL-8	[136]
Clinical studies
APG-157	Oral cancer	A double-blind, randomized, placebo-controlled trial; normal subjects (n = 13) and patients with oral cancer (n = 12); two doses of APG-157 (100 mg or 200 mg) were delivered transorally every hour for 3 h	↑ Antioxidant activity, ↑ anti-inflammatory activity, ↓ IL-1β, ↓ IL-6, ↓ IL-8	[137]
Fisetin	Colorectal cancer	A double-blind, randomized placebo-controlled clinical trial, colorectal cancer patients (n = 37) undergoing chemotherapy were assigned to receive either 100 mg fisetin (n = 18) or placebo (n = 19) for 7 consecutive weeks	Improvement of inflammatory status, ↓ IL-8, ↓ hs-CRP	[138]
Green tea	Prostate cancer	Exploratory, open-label, phase II trial; men with prostate cancer (n = 113) were randomized to consume six cups daily of brewed green tea, black tea, or water (control) prior to radical prostatectomy	↓ NF-κB inflammatory pathway	[139]
Soy	Breast cancer	Randomized, placebo-controlled study; women with early-stage breast cancer (n = 140); soy protein supplementation (n = 70) or placebo (n = 70) for 7 to 30 days	↑ Cell cycle and proliferation, ↑ FGFR2, ↑ E2F5, ↑ BUB1, ↑ CCNB2, ↑ MYBL2, ↑ CDK1, ↑ CDC20	[141]

↑ increased/activated; ↓, decreased/inhibited