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.