Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios

Table 1 Various synthetic and natural peroxisome-proliferator-activated receptor gamma agonist used in experimental and clinical trials for hepatocellular carcinoma

Agonist name	Drug bank/ PubChem ID	Model	Concentration/dose of agonist	Effects	Ref.
Synthetic agonists
Pioglitazone	DB01132	In vivo (Rats, and Mice)	3 mg/kg; 10 mg/kg	Reduced HCC progression and decreased tumor size and volume	[44]
Rosiglitazone	DB00412	In vivo (Orthotopic Mice)In vitro (MHCC97L, and BEL-7404)	50 µmol/L	Decreased HCC migration, and invasiveness	[25]
		In vitro (HepG2 and PC3)	0.1, 1, 10, 100 µmol/L	Reduced cancer growth, Increased apoptosis	[49]
		In vitro (HepG2 and Hep3B)	80 µmol/L	Restricted the oncogenic activity of SEPT2	[50]
Telmisartan	DB00966	In vitro (HLF, HLE, HuH-7, PLC/PRF/5, and HepG2)	10, 50 or 100 µmol/L	Inhibit proliferation, induce cell cycle arrest	[53]
		In vivo (Mice)	15 mg/kg	Reversed malignant anomalies, antioxidant, anti-inflammatory	[54]
Troglitazone	DB00197	In vitro (Hep G2, HuH-7, KYN-1, and KYN-2)	5, 10, 25 µmol/L	Reduced cell proliferation and increased apoptosis	[56]
		In vitro (HepG2)	5, 10, 20, 40, 80, and 100 µmol/L	Apoptosis and growth inhibition	[57]
		In vitro (Hep G2, HuH-7, KYN-1, and KYN-2)	5, 10, and 25 µmol/L	Inhibited DNA synthesis, cell cycle growth, and α-fetoprotein levels	[58]
		In vitro (PLC/PRF/5, and HuH-7)	5, 10, 20, 40, 60, 80, and 100 µmol/L	Reduced cell proliferation and increased apoptosis	[59]
		In vitro (HLF, HAK-1A, HAK-1B, and HAK-5)	10, 20, 30, 40, and 50 µmol/L	Reduced cell proliferation and increased apoptosis	[19]
Saroglitazar	DB13115	In vivo (Mice)	4 mg/kg	Reduced inflammation in hepatic lobules, hepatocellular ballooning, and steatosis	[61]
		In vivo (Rats)	4 mg/kg	Improved lipid profile, and histopathological changes	[62]
Natural agonists
Cannabinol, Cannabinoids	DB14737	In vitro (HepG2 and HUH-7); In vivo (Mice)	8 µmol/L; 15 mg/kg	Increased apoptosis, autophagy, anti-proliferative	[66]
		In vitro (HEK-293T and Neuro-2a); In vivo (Mice)	1, 5, 10, 25 µmol/L; 20 mg/kg	Antitumor, antioxidant, anti-inflammatory	[68]
Capsaicin	DB06774	In vivo (Rats)	0.5 and 1 mg/kg	Inhibit hepatic injury, and collagen deposition, anti-inflammatory	[71]
Curcumin	DB11672	In vivo (Rats)	20 mg/kg	Attenuated histopathological, serological, proliferative, and apoptotic parameters	[77]
		In vitro (H22); In vivo (Mice)	5, 10, 20, 40, and 80 µmol/L; 50, 100 mg/kg	Antiproliferative, decrease tumor growth, induce apoptosis	[78]
		In vivo (Mice)	150 mg/kg	Reduced inflammation, and tumor size	[79]
		In vivo (Rats)	0.5, 1, 2, 5, 10, 15, and 20 ng/mL	Interrupted TGFβ signaling, activated hepatic stellate cells	[80]
		In vitro (SMMC7721 and Huh-7)	10, 20, 40, 80, and 160 µmol/L	Suppressed cellular proliferation	[82]
Hesperidin	DB04703	In vivo (Rats)	50 and 100 mg/kg	Suppressed TGFβ signaling and hepatocarcinogenesis	[85]
		In vivo (Rats)	200 mg/kg	Inhibited PI3K/Akt pathway, Antioxidant	[86]
		In vitro (HepG2); In vivo (Rats)	100 µmol/L; 150 mg/kg	Inhibited Wnt3a/5a signaling pathway, anti-inflammatory	[87]
Hispidulin	DB14008	In vitro (SMMC7721 and Bel7402); In vivo (mouse tumor xenograft)	10 and 20 µmol/L; 20 and 40 mg /kg	Anticancerous, inhibited cell migration	[89]
		In vitro (NCI-H460 and A549)	4, 8, 15, 30, and 60 µmol/L	Induced ROS-mediated apoptosis, anti-cancerous	[90]
Isoflavone	DB12007	In vivo (Bel-7402 and SK-Hep-1)In vivo (Mice)	75 and 12 µmol/L resp.; 25 and 7.5 mg/kg resp.	Anti-inflammatory, anti-tumorigenic, reduced the size and volume of tumor	[94]
		In vitro (Hepa 1-6 cells)	1, 5, 10, 15, 20, 25, 50, 75, and 100 μmol/L	Antitumorigenic and antiproliferative	[95]
		In vitro (HCC-LM3, SMMC-7721, Hep3B, Bel-7402, and Huh-7)In vivo (Mice)	40, 60, and 80 μmol/L; 20, 40, and 80 mg/kg	Suppressed aerobic glycolysis and increased apoptotic rate	[96]
Oroxyloside	14655551	In vitro (HepG2) and SMMC-7721); In vivo (Mice)	100, 200, and 300 μmol/L; 90 mg/kg	Cell cycle arrest and growth repression	[100]
Resveratrol	DB02709	In vivo (Rats)	100 mg/kg	Antioxidant, anti-inflammatory, anticancer	[101]
		In vitro (HepG2); In vivo (Rats)	7.81, 15.63, 31.25, 62.5, 125, and 250 µg/mL; 20 mg/kg	Attenuated histopathological, serological, proliferative, and apoptotic parameters	[102]
Miscellaneous
Avicularin	5490064	In vitro (HuH-7)	25, 50, and 100 µg/mL	Decreased the cell migration and invasiveness	[107]
Honokiol	72303	In vitro (HEK-293 and 3T3-L1); In vivo (Mice)	1, 3, and 10 μmol/L; 100 mg/kg	Activated PPARγ/RXR heterodimers; Reduced hyperglycemia	[108]
Chrysin	DB15581	In vitro (MDA-MB-231 and HepG2)In vivo (Mice)	10 µmol/L; 10 mg/kg	Increased apoptosis	[112]
Quercetin	DB04216	In vitro (HepG2 and SMCC-7721); In vivo (Mice)	0.05, 0.1, and 0.15 mmol/L; 40 mg/kg	Promoted the autophagy	[114]
		In vitro (PATU-8988 and PANC-1)	20, 40, 80, and 160 µmol/L	Suppressed HCC via STAT3 pathway	[117]
		In vitro (LM3); In vivo (Mice)	40, 80, and 120 µmol/L; 100 mg/kg	Reduced invasiveness, Cell cycle regulation	[118]
Clinical trials
		Population type	No. of patients
Thiazolidinediones	NA	Hongkong	1153	Reduce the synergistic effect of diabetes with liver disorders; Reduced risk of HCC	[38],[39],[40],[41]
		Taiwanese	77396
			32891
			76349
Pioglitazone	DB01132	Chinese	75	Blocked RAGE signaling; Reduced HCC	[45]
		Japanese	85	Reduced growth and invasion of HCC cells	[46]
		Thai	10000	Reduced risk of HCC	[47]
Rosiglitazone	DB00412	French	44	Reduced NASH activity and ballooning score, Ameliorated histopathological aberrations	[51]
Saroglitazar	DB13115	Indian	30	Improved glycemic index and liver stiffness	[63]
			90	Improved fibrosis score	[64]
Isoflavone	DB12007	Japanese	302	Antioxidant, reduced risk of HCC	[97]
			191	Antioxidant, reduced risk of HCC	[98]

Akt/PKB: Protein kinase B; HCC: Hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis; PI3K: Phosphoinositide 3-kinase; PPARγ: Peroxisome proliferator-activated receptor gamma; RAGE: Receptor for advanced glycation end products; ROS: Reactive oxygen species; RXR: Retinoid X receptor; SEPT2: Septin 2; STAT3: Signal transducer and activator of transcription 3; TGFβ: Transforming growth factor beta; Wnt: Wingless-related integration site.