Table 1.

Chemopreventive activity of rhein in different cancers.

Cancer	In Vitro/In Vivo /Ex Vivo	Model	Mechanism of Action	References
Breast cancer	In vivo	4T1 xenograft mice	Caspase-3, -8, -9↑, TNF-α↑, IL-6↑	[146]
	In vitro and in vivo	MCF-7, SK-Br-3, and MDA-MB-231 cells	p-EGFR↓, p-ΜΕΚ↓, p-ERK↓	[46]
		MCF-7 injected BALB/c athymic mice
	In vitro	SK-Br-3	p-HER-2↓, NF-κB↓, p53↑, p21↑	[147]
	In vitro	MCF-7	Cleaved caspase↑, p-Akt↓, FOXO3a↑, Bim↑	[144]
	In vitro	MCF-7, MDA-MB-435s	PI3K↓, p-Akt↓, p-ERK↓, NF-κB↓, HIF-1α↓, EGF↓	[138]
			Hsp90α↓, COX-2↓, HER-2↓, VEGF(165)↓, p-I-κB↓
	In vitro	MDA-MB-231	Beclin-1↑, LC3-II/LC3-I↑, p62↓	[148]
Cervical cancer	In vitro	HeLa	MAPK↑, JNK↑, p-ERK↑,	[48]
			cleaved PARP↑, Caspase-3, -7↑
	In vitro	HeLa	β-catenin↓, S phase arrest↑	[111]
	In vitro	CaSki	Cytc↑, Caspase-3, -8, -9↑, Fas↑, p53↑, p21↑, Bcl-2↓,	[149]
			ΔΨm↓, cleaved Bid↑, cleaved PARP↑
Colon cancer	In vitro	Caco-2	p-ERK1/2↑ (at higher concentrations of rhein)	[150]
	In vitro	HT29, HCT116, Colo205, SW620	HIF-1α↓, PD-L1↓, VEGF↓, COX-2↓, galectin-1↓	[98]
	In vitro	HCT116, SW620	p-STAT3↓	[151]
Glioma	In vitro	F98	ERK1/2↓	[152]
	In vitro	T98G, U87, U251	Ac-K100↑, NDRG1↑	[153]
Leukemia	In vivo	EU-1 injected SCID mice	MDM2↓, p53↑	[154]
	In vitro	HL-60	Cleaved caspase↑, cleaved PARP↑, cleaved Bid↑, ΔΨm↓	[145]
	In vitro	NB4	p-ERK↑, Caspase-3↑	[155]
Liver cancer	In vitro and in vivo	HepG2, HepG2 injected BALB/c-nu mice	β-catenin↓, S phase arrest↑	[111]
	In vitro	HepG2	CD95↑, p53↑, p21/WAF↑, mCD95L↑, sCD95L↑	[96]
	In vitro	BEL-7402	c-Myc↓, Caspase-3↑, S phase arrest↑	[54]
	In vitro	HepG2	p-Akt↓, FOXO↑, Bim↑, CHOP↑, p-eIF2α↑, p-ERK↓,	[144]
			Caspase-3, -8, -9↑
	In vitro	HepaRG	ROS↑, ΔΨm↓, Bcl-2↓, Cyclin A↓, S-phase arrest↑	[97]
	In vitro	SMMC-7721, SMMC-7721/DOX	ATP synthesis↓, inner ΔΨm↓	[156]
	In vitro	HepG2, Huh7	ROS↑, p-c-Jun↑, Caspase-3↑	[55]
Lung cancer	In vitro and in vivo	PC-9, H460, A549, H460 xenograft mice	STAT3↓, Bax↑, Bcl-2↓, G2/M phase arrest↑	[157]
	In vitro	A549	p-PI3K↓, Akt↓, mTOR↓, Bcl-2↓	[158]
	In vitro	A549	G0/G1 phase arrest↑, GADD153↑, GRP78↑, Cyt c↑,	[110]
			Caspase-8↑, Bax↑,Bcl-2↓, Cleaved Bid↑, Cyclin D3↓,
			Cyclin E↓, CDK-4↓, CDK-6↓, ROS↑, p53↑, p21↑, ΔΨm↓
Nasopharyngeal cancer	In vitro	NPC	GRP78↑, ATF6↑, CHOP↑, ROS↑,	[49]
			Caspase-3, -8,-9↑
Ovarian cancer	In vitro	SKOV3-PM4	Rac1↓, ROS↓, MAPK↓,	[53]
			TIMP-1↑, TIMP-2↑,AP-1↓
	In vitro	A2780, OV2008	MMP↓	[159]
Pancreatic cancer	In vitro and in vivo	AsPC-1, Patu8988T,	p-STAT3↓	[52]
		BxPC-3,PANC-1 injected BALB/c athymic mice
	In vitro and in vivo	AsPC-1, BxPC-3, HPAF-2, MiaPaCa2, Panc-1,	HIF-1α↓, PFK-1↓, HK-II↓, Glut-1↓	[160]
		MiaPaCa2 injected athymic Balb/c mice
Oral cancer	In vivo	SCC-4	p53↓, cyclin A & E↓, ER Ca2+↑, ROS↑,	[43]
			Caspase-3, -8, -9↑, Bcl-2↓, Cyt c↑
	In vitro	SCC-4	MMP-9↓	[50]

↑: Upregulated; ↓: Downregulated.