Table 1.
Summary of preclinical studies with redifferentiation strategy for radioactive-iodine (RAI) refractoriness in differentiated thyroid cancer
| Target | Compound | Type of study | Result | Reference |
|---|---|---|---|---|
| Autophagy | Digitalis-like compounds (Digoxin, Digoxigenin, Proscillaridin A, Lanatoside C, Strophantin K) | In vitro |
TTF-1, TTF-2, PAX-8, Tg ↑ NIS ↑ 125I uptake ↑ |
182, 183 |
| BRD4 | JQ1 | In vitro, In vivo | NIS ↑ 131I uptake ↑ |
186 |
| BRAF | PLX4720 | In vivo |
NIS, TPO, Tg, TSHR, PAX-8, TTF-1 ↑ NIS ↑ 124I uptake ↑ 131I cytotoxicity ↑ |
58 |
| DNA methylation | 5-aza-2'-deoxycytidine | In vitro |
NIS ↑ 125I uptake ↑ |
132 |
| 5-azacytidine | In vitro |
NIS ↑ 125I uptake ↑ |
135 | |
| ERRɣ | Compound 35 | In vitro, In vivo | NIS, TPO, TSHR, Tg ↑ 124I, 125I uptake ↑ 131I cytotoxicity ↑ |
177 |
| DN200434 | In vitro, In vivo | NIS, TPO, TSHR, Tg ↑ 124I, 125I uptake ↑ 131I cytotoxicity ↑ |
176 | |
| GSK5182 | In vitro | NIS (membrane) ↑ 125I uptake ↑ 131I cytotoxicity ↑ |
175 | |
| HDAC | AB2, AB3 and AB10 | In vitro | NIS, PAX-8, TTF-1, TTF-2, TSHR ↑ | 152 |
| APHA compound 8 | In vitro | NIS ↑ 125I uptake ↑ |
148 | |
| Apicidine | In vitro | NIS ↑ 125I uptake ↑ |
148 | |
| Depsipeptide | In vitro, In vivo | NIS, Tg, TPO ↑ 125I uptake ↑ |
143, 144 | |
| Entinostat | In vitro | 125I uptake ↑ | 149 | |
| Panobinostat (LBH589) | In vitro | NIS ↑ 125I uptake ↑ 131I cytotoxicity ↑ |
145 | |
| Sodium butyrate | In vitro | NIS, PAX-8 ↑ | 150 | |
| Trichostatin A | In vitro |
NIS ↑ NIS, Tg, TPO ↑ |
146, 150, 151 | |
| Valproic acid | In vitro |
Tg ↑ NIS ↑ 125I uptake ↑ |
144, 147, 148 | |
| Vorinostat | In vitro | NIS, TSHR, TPO ↑ | 16 | |
| LXR | Dendrogenin A | In vitro | NIS, TPO, TSHR, Tg ↑ 123I, 131I uptake ↑ |
173 |
| MAPK | CTOM-DHP | In vitro, In vivo | NIS, TPO, Tg, TSHR, PAX-8, TTF-1 ↑ 123I, 125I uptake ↑ 131I cytotoxicity ↑ Tumor growth ↓ |
30 |
| K905-0266 | In vitro, In vivo | NIS, TPO, Tg, TSHR, PAX-8, TTF-1 ↑ 125I uptake ↑ 131I cytotoxicity ↑ Tumor burden ↓ |
84 | |
| MAPK, SAPK/JNK | Sunitinib | In vitro | NIS, TPO, Tg, TSHR, PAX-8↑ | 81 |
| MEK | CH5126766 | In vivo | NIS ↑ 124I uptake ↑ 131I cytotoxicity ↑ Tumor growth ↓ |
83 |
| PD0325901 | In vivo |
NIS, TPO, Tg, TSHR, PAX-8, TTF-1 ↑ NIS ↑ 124I uptake ↑ 131I cytotoxicity ↑ |
58 | |
| Selumetinib | In vivo | NIS ↑ 124I uptake ↑ 131I cytotoxicity ↑ Tumor growth ↓ |
83 | |
| U0126 | In vitro | TSHR, NIS, Tg ↑ | 56 | |
| mTORC1 | Rapamycin | In vitro | NIS ↑ TTF-1, TTF-2, PAX-8, TSHR ↑ 125I uptake ↑ |
92 |
| mTORC1/mTORC2 | Torin2 | In vitro | NIS ↑ | 94 |
| Notch | Resveratrol | In vitro | NIS, TTF-1, TTF-2, PAX-8 ↑ | 96 |
| PI3K | LY294002 | In vitro | NIS ↑ 125I uptake ↑ |
89 |
| PPARɣ | Pioglitazone, Rosiglitazone | In vitro | 125I uptake ↑ | 168, 169 |
| Rosiglitazone | In vitro | 125I uptake ↑ | 148 | |
| Troglitazone | In vitro | NIS, Tg ↑ 125I uptake ↑ |
168, 169 | |
| Retinoic acid receptor | 13-cis retinoic acid | In vitro | 131I uptake ↑ | 163 |
| All-trans retinoic acid | In vitro |
NIS, Tg ↑ NIS ↑ 125I uptake ↑ |
148, 164-166 | |
| All-trans retinol | In vitro |
NIS ↑ 125I uptake ↑ |
148 | |
| Reverse transcriptase enzyme | Nevirapine | In vitro, In vivo | NIS, PAX-8, TSHR ↑ 125I uptake ↑ |
17, 201 |
| VEGFR, RET, MET, FLT3, AXL | Cabozantinib | In vitro | NIS, TPO, Tg, TSHR ↑ 125I uptake ↑ 18F-FDG uptake ↓ |
80 |
| VEGFR, PDGFR, RET, KIT, FLT | Sorafenib | In vitro | NIS, TPO, Tg, TSHR ↑ 125I uptake ↑ 18F-FDG uptake ↓ |
80 |
Abbreviations: BRD4: bromodomain-containing protein 4; ERRɣ: estrogen-related receptor ɣ; FLT: fms-related receptor tyrosine kinase; 18F-FDG: fluorodeoxyglucose (18F); FLT-3: fms-related receptor tyrosine kinase-3; HDAC: histone deacetylase; LXR: liver X receptor; MAPK: mitogen-activated protein kinase; MET: MNNG HOS transforming gene; NIS: sodium iodide symporter; PAX-8: paired box gene-8; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; PPARɣ: peroxisome proliferator-activated receptor ɣ; Tg: thyroglobulin; TPO: thyroperoxidase; TSHR: thyroid-stimulating hormone (TSH) receptor; TTF-1: thyroid transcription factor-1; TTF-2: thyroid transcription factor-2; VEGFR: vascular endothelial growth factor receptor.