Table 1.
Emerging agents for inducing HCC differentiation
| Compounds | Mechanisms | Functions | Cell lines and models | Ref. |
|---|---|---|---|---|
| ATRA | inactivation of PI3K/AKT pathway enhancing GSK-3β-dependent phosphorylation of β-catenin | (i) Induce differentiation | (i) Cell lines (SMMC-7721, BEL-7402 and HepG2) | [27,39] |
| (ii) Inhibit proliferation | ||||
| (iii) Enhance the drug sensitivity to docetaxel | ||||
| ATRA + cisplatin | Inhibition of AKT phosphorylation in Thr308 | (i) Induce differentiation and apoptosis | (i) Cell lines (Huh7 and CSQT-2) | [40] |
| (ii) Inhibit proliferation and migration | (ii) Cell-derived xenograft (HuH7 and CSQT-2) | |||
| (iii) Enhance the drug sensitivity to cisplatin | ||||
| (iiii) Inhibit HCC metastasis | ||||
| ATRA + sorafenib | Inhibition of AKT phosphorylation | (i) Induce differentiation | (i) Cell lines (Huh7) | [41] |
| (ii) Inhibit proliferation | (ii) Patient-derived xenograft | |||
| (iii) Enhance the drug sensitivity to sorafenib | ||||
| (iiii) Inhibit HCC growth | ||||
| As2O3 | Downregulation of the GLI1 expression | (i) Induce differentiation | (i) Cell lines (Huh7 and Hep3B) | [42] |
| (ii) Inhibit self-renewal ability | (ii) Cell-derived xenograft (Huh7 and Hep3B) | |||
| (iii) Inhibit tumorigenic capacity and HCC recurrence | ||||
| OSM | Unknown | (i) Induce differentiation | (i) Cell lines (Huh1 and Huh7) | [43] |
| (ii) Enhance the drug sensitivity to 5-FU | (ii) Cell-derived xenograft (Huh1 and Huh7) | |||
| (iii) Inhibit HCC growth | (iii) Patient-derived xenograft | |||
| Rad001 | Inhibition of mTORC1 | (i) Induce differentiation | (i) Cell lines (HepT1, HepG2, Huh6 and Huh7) | [44] |
| (ii) Enhance the drug sensitivity to doxorubicin | (ii) Cell-derived xenograft (Huh7) | |||
| (iii) Inhibit HCC growth | ||||
| A939572 | Inhibition of SCD1 | (i) Induce differentiation | (i) Cell lines (PLC/PRF/5 and Huh7) | [45] |
| (ii) Inhibit self-renewal ability, migration and invasion | (ii) Patient-derived xenograft | |||
| (iii) Enhance the drug sensitivity to sorafenib | ||||
| (iiii) Inhibit HCC growth | ||||
| 5-AZA | CpG demethylation | (i) Induce differentiation | (i) Cell lines (HepG2, Hep3B and Huh7) | [46] |
| (ii) Inhibit tumorigenicity | (ii) Cell-derived xenograft (HepG2 and Hep3B) | |||
| (iii) Enhance the drug sensitivity to sorafenib | ||||
| (iiii) Inhibit HCC growth |
Abbreviations: ATRA, all-trans retinoic acid; As2O3, arsenic trioxide; OSM, oncostatin M; SCD1, stearoyl-CoA desaturase-1; 5-AZA, 5-azacytidine.