Table 1.

Apoptotic and Tumorigenic Effects of Emodin.

Main effect	Model	Cell line or species	Agent/dose/administration route	Mechanism	Reference
Apoptosis	Human HCC	HepaRG	Emodin*; 0-80 µM, 0-48 h IC50 ≈ 40/80 µM at 48/24 h	Mitochondrial mediated apoptosis by ↑ROS*** and cell cycle arrest (at S and G2/M phases)	Dong et al 30
		HepG2 and normal human L02 hepatocytes	Emodin*; 0.14-100 µM, 48 h HepG2 IC50 ≈ 44 µM; L02 IC50 ≈ 22 µM Emodin derivative**; 0-10 µM, 48 h HepG2 IC50 ≈ 5 µM; L02 IC50 ≈ 14 µM	Mitochondrial mediated apoptosis***; cell arrest at G0/G1 phase (in HepG2)***	Yang et al 34
		HepG2	Emodin*; 1-100 µM, 0-72 h IC50 ≈ 20 µM, 72 h	MAPK regulation (DEGs association; 20 uM)	Zhou et al 29
		HepG2	Emodin; 50 or 100 μM, 0-48 h	Cyp-D↑ regulated by ROS***, p-ERK↓***	Zhang et al 37
		In vitro: SMMC-7721	In vitro: Emodin*; Apoptosis: 0-200 µM, 0-48 h IC50 ≈ 50 µM, 48 h	↓PI3K (↓p-Akt)***; ↑MAPK (↑p-ERK, ↑p-p38, mild↓JNK)***	Lin et al 19
	Human liver fibrosis	LX2 (human hepatic stellate-model for liver fibrosis)	Aloe Emodin; 10 or 20 µM, 72 h	Mitochondrial mediated apoptosis, ↓PI3K signaling pathways, ↓TNF	Cai et al 41
	Normal human liver	L02	Emodin; 0-80 µM, 0-24 h IC50 ≈ 60-80 µM, 24 h	↑Autophagy (protective role) by ↓p-PI3K/p-AKT/p-mTOR to inhibit apoptosis	Zheng et al 43
	Human colon cancer	HCT116	Emodin; 10, 25, and 50 µM, 0-24 h IC50 ≈ 20 µM, 24 h	Inhibition of fatty acid synthesis (FASN)***, ↓PI3K/Akt (25 uM) signaling pathways	Lee et al 49
		HCT116	Emodin, 15, 30, 60 μg/ml, 24 h	↓PI3K, ↓p-AKT, ↓VEGFR2	Dai et al 20
		SW620 and HCT116	Emodin, 10, 20, 40 uM, 24 h	Apoptosis***	Zhang et al 22
		CACO-2	Emodin*; Cell viability: 0-200 µM, 24 h; anti-tumor effects: 15-60 µM) IC50 ≈ 35 µM	Mitochondrial mediated apoptosis***, ↓PI3K/Akt (phospho-proteins) signaling pathway***, induce G2/M cell cycle arrest***	Ma et al 28
		DLD-1 and COLO-20	Emodin*; cell viability: 0-80 μM, 0-72 h All other experiments: 15-18 μM (IC50), 0-48 h	Mitochondrial mediated apoptosis via ↓MAPK/JNK, PI3K/AKT, NF-κβ and STAT pathways	Saunders et al 27
		SW620 and HT29	Aloe Emodin*; 0-40 μM, 0-72 h IC50 ≈ 40 µM, 72 h	ER stress by ↑ROS***; mitochondrial mediated apoptosis***	Cheng and Dong 39
		HCT116 and LOVO	Emodin; Cell viability: 0-320 µM, 0-48 h All other experiments; 0-40 µM, 24 h IC50 ≈ 40, 48 h	Mitochondrial mediated apoptosis by autophagy-ROS dependent induction***; mitochondrial dysfunction	Wang et al 46
Main effect	Model	Cell line or species	Agent/dose/administration route	Mechanism	Reference
		HT-29	Emodin* and silica nanomaterials loaded with emodin, 0-80 μM, 0-48 h	Mitochondrial mediated apoptosis, ↓PI3K/Akt, ↑p-ERK, ↑auophagy (↑LC3A/B)	Janicke et al 48
		In vitro: LS1034	Emodin, 0-50 µM, 0-48 h	Mitochondrial mediated apoptosis by ↑ROS	Ma et al 32
	Human pancreatic cancer	MIAPaCa-2 and PANC-1	Aloe Emodin*; 0-100 µM, 48 h IC50 ≈ 40 µM	Mitochondrial mediated apoptosis and autophagy dose-dependently; sub-G1 cell cycle arrest	Du et al 40
		PANC-1 and MiaPaCa2	Emodin, 10-160 µM, 72 h (apoptosis) Emodin, 40 µM; gemcitabine, 20 µM	↓Survivin, XIAP, NF-κB, and IKKβ. ↑Caspase-3/9 and IκB-α	Tong et al 31
		PANC-1 and BxPC-3	In vitro: emodin*; 0-90 µM, 0-72 h EGFR inhibitor Afatinib*; 20 nM, 0-72 h	↓STAT3 (emodin with or without afatinib)***	Wang et al 23
		20 BALB/c nude mice (5 mice/group) subcutaneously injected with PANC-1 cells	In vivo: emodin and afatinib, 50 mg/kg, oral, 4 weeks after tumor reached 30-50 mm3. Vehicle: saline
↓Tumorigenesis	Human HCC	In vitro: HepG2	In vitro: emodin; 10, 20, or 100 nM, 0-36 h	Inhibited VEGFR2-AKT-ERK1/2 signaling pathway*** and ↑miR-34a	Bai et al 13
		In vivo: 30 male BALB/c nude mice subcutaneously injected with HepG2 cells	In vivo: emodin; 1 or 10 mg/kg, hypodermic injection, daily/10 days
		In vitro: HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5	In vitro: emodin*; 0-40 μM, 0-72 h optimal: emodin 20 µM and sorafenib*; 2 µM	↓Cholesterol*** to sensitize cells via ↓Akt*** and STAT3*** by inhibiting sterol regulatory element-binding protein-2 (SREBP-2)	Kim et al 15
		In vivo: BALB/c-nude mice xenografted with HepG2 or SK-HEP-1	In vivo: emodin*; 10 mg/kg, i.p. and/or sorafenib*; 5 mg/kg, i.p., daily/3 weeks after tumor reached 250 mm3
		HepG2	Emodin derivative**; 0-1 µM, 48 h	↓Migration*** (no mechanism)	Yang et al 34
		In vivo: 15 male BALB/c-nu nude mice (5 mice/group) subcutaneously injected with SMMC-7721 cells	In vivo: Emodin*; 25 or 50 mg/kg, i.p., everyday for 2 weeks after tumor volume 75-100 mm3	No toxicity or body weight changes ↓ALT, AST, AKP, GGT, Cr and BUN	Lin et al 19
		HepG2	β-dihydroartemisinin-emodin	Mitochondrial mediated apotosis; inhibited G1 to S cell cycle progression; inhibited cell migration by ↓survivin	Li et al 42
Main effect	Model	Cell line or species	Agent/dose/administration route	Mechanism	Reference
	Colon cancer	In vitro: HT29 and RKO (human)	In vitro: emodin; MTT: 0-100 μM, 0-48 h All other experiments: 5, 10, 20 µM IC50 ≈ 40/80 μM 48/24 h	↓matrix proteins and VEGF***.	Gu et al 17
		In vivo: 30 male BALB/c nude mice (15 mice/group) pretreated with emodin before subcutaneous RKO cell injection into inguinal region, sacrificed after 4 weeks	In vivo: 40 mg/kg, P.O., 7 day pretreament	↓EMT by Wnt/β-Catenin Pathway inactivation and by ↑E-cadherin and ↓N-cadherin, Snail, and b-catenin (mRNA)***
		100 WAG/Rij rats implanted intraperitoneal (ip) or subcutaneous (sc) CC-531 rat colon cancer cells for 28 days then treated	Emodin in 5% polyvinylpyrrolidone (PVP) and 0.9 % sodium chloride; 2.5 or 5 mg/kg; intravenous (iv) port catheter or ip injection, 7 days	N/A	Hohn et al 14
		30 male BALB/c nu/nu mice xenografted with LS1034; subcutaneously injected into flank	In vivo: emodin*,40 mg/kg, ip, 1x every 3 days/4 weeks after tumor reached 200 mm3. Vehicle: 1% DMSO	N/A	Ma et al 32
		HCT116	Emodin, 20, 40, 80 mg/kg, ip, daily/3 weeks	↓PI3K, ↓p-AKT, ↓VEGFR2	Dai et al 20
		30 Male BALB/c mice (15/group); AOM/DSS model of colitis-associated intestinal tumorigenesis	Emodin; 50 mg/kg, gavage, 2 or 4 weeks	14 weeks (in tumor microenvironement): ↓inflammatory cell (i.e. CD11b+ and F4/80+) recruitment, cytokine (i.e. TNFa, IL1a/b, IL6, CCL2, CXCL5) and pro-inflammatory enzymes (i.e. COX-2, NOS2); ↑ CD3+ T cell recruitment. ↓Bleeding and diarrhea	Zhang et al 22
		HCT116 and LOVO (human)	Emodin; Cell viability: 0-320 μM, 0-48 h All other experiments; 0-40 μM, 24 h IC50 ≈ 40 μM, 48 h.	Mitochondrial mediated apoptosis by autophagy-ROS dependent induction***; mitochondrial dysfunction	Wang et al 46
	Human pancreatic cancer	In vitro: AsPC-1, BxPC-3, HPAF-2, MiaPaCa2, and Panc-1 (all human). Cells treated with agents with immediate 6 h hypoxic incubation	In vitro: emodin (0-200 μM) and rhein (0-200 μM) alone, 6 h	HIF1A inhibtion (all)*** by ↓Akt and ERK1/2 pathways*** (in vitro: MiaPaCa2; in vivo)	Hu et al 21
		In vivo: 30 male athymic BALB/c mice (10 mice/group) subcutaneously implanted with MiaPaCa2 cells for 8 weeks	In vivo: emodin (50 mg/kg/day) and/or rhein (50 mg/kg) in PBS; gavage, last 4 weeks (1x/5 days a week)
		In vitro: PANC-1 and BxPC-3 (human)	In vitro: emodin*; 0-90 µM, 0-72 h Afatinib *; 20 nM, 0-72 h	↓STAT3 (emodin with or without afatinib)***	Wang et al 23
		In vivo: 20 BALB/c nude mice (5 mice/group) subcutaneously injected with PANC-1 cells	In vivo: emodin and EGFR inhibitor afatinib,50 mg/kg, oral, 4 weeks after tumor reached 30-50 mm3. Vehicle: saline
		40 female athymic BALB/c nu/nu mice with surgical orthotopic implantation of SW1990 cells (10 mice/group)	Emodin in DMSO; 20, 40, and 80 mg/kg, i.p., 3x a week/3 weeks	Inhibition*** of angiogenesis via TGF-β/Smad signaling pathway (↓TGF-β1, ↓Angptl4, ↑SMAD4). ***↓oncogenic and angiogenesis-associated miR-155 and miR-210; ↑antiangiogenic miR-20b***	Lin et al 18
		In vitro: SW1990 (human)	In vitro: emodin; 0-40 μM, 0-48 h	Inhibited EMT and invasion via ↑miR-1271***; inhibited liver metastasis of pancreatic cancer via same mechanism	Li et al 16
	Human pancreatic liver metastasis	In vivo: SW1990 cells injected into spleens of 45 nude mice (15 mice/group)	In vivo: emodin; 20 or 50 mg/kg; gavaged for about 3 weeks after 8 days of tumor establishement. Sacrificed 6 weeks later.
		Agent dissolved in DMSO*	((R)-1-(3-(4,5-Dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yloxy)propoxy)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate) in DMSO**	Dose-dependent***