TABLE 1.

Anticancer perspectives of polyphenols along with their mechanism of action and signaling pathway.

Compound	Cancer type	Model	Mechanism of action	Target	References
Quercetin	Thyroid	SW480	↑ apoptosis	Pro-NAG-1/GDF15	(Hong et al., 2021a; Hong et al., 2021b)
		HEK293
		U2OS
		BT-20 in vitro
	Breast	MCF-7	↑ autophagy	Akt-mTOR	Jia et al. (2018)
		MDA-MB-231 in vitro
		MCF-7 in vitro	↑ apoptosis	PI3K/Akt/mTOR	Li et al. (2018)
		MDA-MB-231 in vitro	↑apoptosis cell cycle arrest	Foxo3a	Nguyen et al. (2017)
		MDA-MB-231 in vitro	cell cycle arrest	Akt/AMPK/mTOR	(Rivera rivera et al., 2016; Lu et al., 2018)
	Oral	HCCLM3 in vitro	↓invasion	p-Akt1, MMP-2.MMP-9	Lu et al. (2018)
			↓migration
		Male Syrian hamsters in vivo	↑apoptosis	NF-κB	Zhang et al. (2017)
	Liver	PC3	↑apoptosis cell cycle arrest	PI3K, AKT, ERK1/2	Erdogan et al. (2018)
		LNCaP in vitro
	Ovarian	A2780S in vivo	↑ apoptosis	Caspase-3, -9, MCL-1, Bcl-2, Bax	Gao et al. (2012)
			↓ angiogenesis
EGCG	Breast	MCF-7 in vitro	↓proliferation	P53 and Bcl-2	Huang et al. (2017)
			↓apoptosis
		T47D in vitro	↓proliferation	PI3K/AKT	Moradzadeh et al. (2017)
			↑apoptosis
		SUM-149	↑apoptosis	ER-α36	Pan et al. (2016)
		SUM-190
		MDA-MB-231 in vitro
	Ovarian	SKOV3 in vitro	↓proliferation	AQP5, NF-κB, p65, IκBα	Yan et al. (2012)
			↑apoptosis
	Leukemia	NB4 in vitro	↓proliferation cell cycle regression	DNMT1, DNMT3a, DAPK1	Shi et al. (2018)
		NB4 in vitro	↑apoptosis	SHP-1-p38αMAPK-Bax	Gan et al. (2017)
		HL-60 in vitro	↑apoptosis	Bcl-2, caspase-3	Han and Kim, (2009)
	Lymphoma	BCBL-1	↑apoptosis ↑autophagy	MAPK	Tsai et al. (2017)
		BC-1 in vitro
		Jeko-1	↑apoptosis	Fas, Bax, Bcl-2	Wang et al. (2015b)
		Raji in vitro
	Renal	786-0ACHN in vitro	↓cell invasion	MMP-2, MMP-9	Chen et al. (2016)
		Caki-1 in vitro	↓suppression inactivation	Src, JNK	Sato et al. (2013)
	Head and neck	Tu686 in vitro	↑apoptosis	Bim, p21, p27, Bcl-2	Haque et al. (2015)
	Oral	C3H/HeJ	↑cell proliferation	HGF/c-Met	Koh et al. (2011)
		SCC VII/SF in vitro	↓migration
			↓invasion
		SCC-9 in vitro	↓cell growth	MMP-9	Chen et al. (2011)
			↓invasion
	Thyroid carcinoma	TT TPC-1 ARO in vitro	↓angiogenesis	EGFR/RAS/RAF/MEK/ERK	Wu et al. (2019)
			↑apoptosis
		8505C in vitro	↑suppression	TGF-β1/Smad	Li et al. (2019)
			↓ invasion
			↓migration
	Osteosarcoma	MG-63	↓cell proliferation cell cycle arrest	miR-1/c-MET	Zhu and Wang, (2016)
		U-2OS in vitro
			↑apoptosis
		MG63	↑apoptosis	miR-126	Jiang et al. (2014)
		U-2OS in vitro
	Glioblastoma	GBM02	↑apoptosis ↑autophagy		Grube et al. (2018)
		GBM15
		GBM16,17 in vitro
	Hepatocellular carcinoma	HCC-LM3	↑cancer cell death	PFK	Li et al. (2016)
		Huh-7
		HepG2
		SMMC-7721 in vivo, in vitro
Curcumin	Pancreatic	Patu8988	cell cycle arrest ↑apoptosis	YAP/TAZ	Zhou et al. (2016)
		Panc-1 in vitro
	Glioblastoma	A172 in vitro	↑autophagy		Lee et al. (2019)
	Breast	MCF-7 in vitro	↑apoptosis	Mcl-1	Koohpar et al. (2015)
Silibinin	Colorectal	CT26 in vitro	↓angiogenesis ↑autophagy	Bax, Caspase-3, COX-2	Sameri et al. (2021)
			↑apoptosis ↓migration
	Glioblastoma	A172 in vitro	↑apoptosis	mTOR, YAP	Bai et al. (2018)
			↓autophagy
	Breast	MCF7 in vitro	↑cell autophagy	BNIP3	Jiang et al. (2015)
	Ovarian	SKOV-3 in vitro	↑ apoptosis	P53, P21	Pashaei-asl et al. (2018)
		A2780 SKOV3 in vitro, in vivo	↓tumor growth	p-ERK, p-Akt	Cho et al. (2013)
Apigenin	Cervical	HeLa in vitro	↓cell-renewal capability	CK2α	Liu et al. (2015)
	Breast	A549 in vitro	↓proliferation	PI3K/Akt	Zhou et al. (2017)
			↑migration ↓invasiveness
		MDA-MD-231 in vitro, in vivo)	cell cycle arrest	cyclin A, cyclin B, CDK1, p21WAF1/CIP1	Tseng et al. (2017)
		MDA-MB-468, 4T1 in vitro	↑immune response	IFN-γ, PD-L1, STAT1	Coombs et al. (2016)
		SKBR3 in vitro	↑apotosis	p-JAK2 and p-STAT3, VEGF	Seo et al. (2015)
	Lung	H1299 H460 in vitro	↓cell proliferation	GLUT 1	Lee et al. (2016b)
			↑apoptosis
	Prostate	PC3 in vitro	cell cycle arrest	p21 and p27; caspases-8,-3, TNF-α	(Shukla et al., 2015; Erdogan et al., 2016)
			↑apoptosis
		DU145 in vitro	cell cycle arrest	IKK—IκBα	Shukla et al. (2015)
			↑apoptosis
			↓tumorigenesis
		PC3-M LNCaP C4-2B in vitro	↓cell proliferation ↓metastases	Smad2/3, Src/FAK/Akt	Mirzoeva et al. (2014)
	Colorectal	SW480 in vitro	↓cell proliferation	Wnt/β-catenin	Xu et al. (2016)
			↓migration
			↓invasiveness
		DLD1	↓cell proliferation ↓migration	NEDD9	Dai et al. (2016)
		SW480 in vitro, in vivo
			↓invasiveness
		HCT116 in vitro	↓proliferation	cyclin B1, Cdc2, Cdc25c	Lee et al. (2014)
			↑apoptosis
			↑autophagy
	Renal cell	ACHN	cell cycle arrest	p53	Meng et al. (2017)
		786–0
		Caki-1 in vitro, in vivo
	Head and neck squamous carcinoma	HSC-3	↓cancer cell markers	CD44, NANOG, CD105	Ketkaew et al. (2017)
		HN-8
		HN- 30 in vitro
Luteolin	Prostate	PC3	↑apoptosis	miR-301	Han et al. (2016)
		LNCaP in vitro
	Hepatocellular carcinoma	SMMC-7721 in vitro	↑apoptosis	BL-2, caspase-8	Cao et al. (2017)
			↑autophagy
	Cholangiocarcinoma	n CCA	cell cycle arrest	JAK/STAT3	Aneknan et al. (2014)
		KKU-M156 in vitro	↑apoptosis
			↓migration
	Pancreatic	BxPC-3 in vitro	↓cell proliferation	GSK-3β, NF-κB, p65	Johnson and Mejia, (2013)
	Colon	Balb/C mice in vivo	↑apoptosis	MMP-2, -9, TIMP-2	Pandurangan et al. (2014)
	Oral	CD44 in vitro	↓invasiveness clonogenicity	IL-6/STAT3	Tu et al. (2016)
	Gastric	MKN45	↑mirnas expression	Notch1, PI3K, AKT, mTOR, ERK, STAT3	Pu et al. (2018)
		BGC823 in vitro, in vivo
		BGC-823	↑apoptosis	miR-34a, Bcl-2	Wu et al. (2015)
		SGC-7901 in vitro
	Neuroblastoma	SH-SY5Y in vitro	cell cycle arrest		Wang et al. (2015a)
			↑apoptosis
	Breast	MDA-MB-231 in vitro, in vivo	apoptosis	STAT3	Yang et al. (2014)
	Glioblastoma	U87MG	↑apoptosis	miR-7-1-3p	Chakrabarti and Ray, (2016)
		T98G in vivo	↑autophagy
Genistein	Breast	MCF-7	cell cycle arrest		Jiang et al. (2018)
		MDA-MB-231 in vitro	↓proliferation
			↑inhibition
	Hepatocellular	Hepa1-6 in vitro	↑apoptosis		Sanaei et al. (2018)
			↓proliferation
	Cervical	HeLa in vitro	↑apoptosis	GRP78, CHOP	Yang et al. (2016b)
	Liver	HepG2 in vitro	↑apoptosis cell cycle arrest	Bax, Bcl-2, caspase-3, 9	Zhang et al. (2019)
Protocatechuic acid	Gastric carcinoma	B16/F10 in vitro	↓cell migration	Ras/Akt/NF-kB	Lin et al. (2011)
			↓invasion
	Breast	MCF-7	↑apoptosis	Caspase-3, 9	Yin et al. (2009)
		A549	↓metastasis
		HepG2	↓invasion
		HeLa
		LNCaP in vitro
Rosmarinic acid	Colorectal	CT26 in vitro	cell cycle arrest	EMT, MMPs, AMPK	Han et al. (2018a)
			↑apoptosis
	Pancreatic	Panc-1	↓cell viability	miR-506, MMP2/16	Han et al. (2019)
		SW1990 in	↓growth
		vitro	↓invasion
			↓migration
	Human melanoma	A375 in vitro	↑apoptosis	ADAM17/EGFR/AKT/GSK3β	Huang et al. (2021)
			↓proliferation
			↓migration
	Breast	Mice	↓inflammation	NF- κB, p53 caspase-3	Mahmoud et al. (2021)
		in vivo	↓angiogenesis
			↑apoptosis
	Head and Neck Squamous Carcinoma	UM- SCC-6	↓cell viability	MAPK/ERK	Tumur et al. (2015)
		UM-SCC-	↓ migration
		10B in vitro	ROS
	Colon	Wistar rats in vivo	↓cell proliferation	IL-6, COX-2, p65	Karthikkumar et al. (2015)
	Gastric	MKN45 in vitro	↓tumorgenesis	miR-155, IL-6/STAT3	Han et al. (2015)
Chlorogenic Acid	Hepatocellular carcinoma	Hep-G2	↑apoptosis	MAPK, NF-κB, TGF-β	Jiang et al. (2021)
		Huh-7 in vitro
	Breast	Females in vivo	↑apoptosis ↓metastasis	NF-κB/EMT	Zeng et al. (2021)
		4T1 in vitro	↑apoptosis	Bax and Bcl-2	Changizi et al. (2020)
	Tumor cells	HepG2 A549 in vitro	↓migration	mTORC2/F-actin	Tan et al. (2019)
			↓invasiveness
			↓tumor growth
	Glioblastoma	G422 in vitro	↑apoptosis	LPS/IFNγ	Xue et al. (2017)
	Leukemia	U937	↑apoptosis		Liu et al. (2013)
		K562 in vitro	↓proliferation
Eupatorin	Breast	4T1 in vivo	↓tumor development	MMP-9, NF-κB, NK1.1, CD8+	Abd Razak et al. (2020)
			↓metastasis
		MCF-7	Cell cycle arrest, invasion, migration	Phospho-Akt	Razak et al. (2019)
		MDA-MB-231 in vitro
		MDA-MB-468 in vitro	cell cycle arrest	CYP1	Androutsopoulos et al. (2008)
	Cervical	HeLa in vitro	cell cycle arrest	p53, p21, Bax	Lee et al. (2016a)
			↑apoptosis
	Leukemia	HL-60	↑apoptosis	c-jun N-terminal kinases	Estevez et al. (2014)
		U937
		Molt-3 in vitro

Symbols: ↑increase, ↓decrease. Abbreviations: ADAM17/EGFR/AKT/GSK3β, a disintegrin and metalloproteinase-17/epidermal growth factor receptor/protein kinase B/Glycogen synthase kinase3β; Akt/AMPK/mTOR, protein kinase B/Adenosine monophosphate-activated protein kinase/mammalian target of rapamycin; Akt-mTOR, protein kinase B/mammalian target of rapamycin; AQP5, aquaporin-5; Bax, Bcl2-Associated X Protein; Bcl-2, B-cell leukemia/lymphoma 2 protein; Bim, B cell lymphoma-2-like 11; BL-2, Burkitt’s lymphoma-2; CD8⁺, cluster of differentiation 8; Cdc2, cell-division cycle 2; CD44, cluster of differentiation 44; CD105, endoglin; CDK1, cyclin-dependent kinase-1; CHOP, cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone; CK2α, catalytic subunit of protein kinase CK2; COX-2, cyclooxygenase-2; CYP1, cytochrome P450 1; DAPK1, death associated protein kinase 1; DNMT1, DNA (cytosine-5)-methyltransferase 1; DNMT3a, DNA methyltransferase 3 alpha; EGFR/RAS/RAF/MEK/ERK, epidermal growth factor receptor/rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase; EMT, epithelial-mesenchymal transition; ERK1/2, extracellular signal-regulated kinase 1/2; ER-α36, estrogen receptor-alpha36; Fas, cell surface death receptor; Foxo3a, forkhead box class O 3a; GLUT 1, glucose transporter 1; GRP78, glucose-regulating protein 78; GSK-3β, glycogen synthase kinase-3 beta; HGF/c-Met, hepatocyte growth factor/c-mesenchymal-epithelial transition factor; IFN-γ, interferon-gamma; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IKK–IκBα, IκB kinase-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; IL-6, interleukin-6; JNK, c-Jun N-terminal kinase; LPS/IFNγ, lipopolysaccharide/interferon-gamma; MAPK, mitogen-activated protein kinase; MCL-1, myeloid cell leukemia 1; miR-1/c-MET, microRNA-1/mesenchymal-epithelial transition factor; miR-126, microRNA-126; miR-301, microRNA-301; MMPs, matrix metalloproteinases; mTORC2/F-actin, mTOR complex 1/filamentous actin; NEDD9, neural precursor cell expressed, developmentally downregulated nine; NF-κB, nuclear factor kappa B; NK1.1, natural killer 1.1; p-ERK, phosphorylated-extracellular signal-regulated kinase; PD-L1, programmed death-1; PFK, phosphofructokinase; pro-NAG-1/GDF15, pro-nonsteroidal anti-inflammatory drug-activated gene-1/growth differentiation factor 15; p21WAF1/CIP1, wild-type activating fragment-1/cyclin-dependent kinase inhibitory protein-1; PI3K/Akt/mTOR, phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin; p-Akt1, phosphorylated-serine/threonine kinase 1; p-JAK2, phosphorylated Janus kinase 2; p-STAT3, phosphorylated signal transducer and activator of transcription 3; SHP-1-p38αMAPK-Bax, Src homology 2 domain-containing protein tyrosine phosphatase 1 mitogen-activated protein kinase; Src, Proto-oncogene tyrosine-protein kinase; STAT1, signal transducer and activator of transcription 1; TGF-β1/Smad, transforming growth factor-β1/suppressor of mothers against decapentaplegic; TIMP-2, tissue inhibitor of metalloproteinase-2; TNF-α, tumour necrosis factor-alpha; VEGF, vascular endothelial growth factor receptor; Wnt, wingless-related integration site; YAP/TAZ, yes-associated protein/transcriptional coactivator with PDZ-binding motif.