Table 1.
Potential therapeutic strategies targeting altered growth factor and intracellular elements in normoxic and hypoxic cancer- and metastasis-initiating cells and their differentiated progenies
| Molecular target | Name of inhibitory agent |
|---|---|
| Hypoxia-activated pro-drug | |
| Hypoxic cancer cells | TH-302 |
| Growth factor signalling elements | |
| EGFR (erbB1) | Anti-EGFR mAb (cetuximab or IMC-C225 (Erbitux®)*, panitumumab (Vectibix®)*, mAb-C225); TKI (gefitinib (Iressa®)*, erlotinib (Tarceva®)*, AG1478) |
| HER-2 (erbB2) | Anti-HER-2 mAb (trastuzumab (Herceptin®)*) |
| IGF-1R | Anti-IGF-1R mAb (robatumumab or R1507); TKI (NVP-AEW541, BMS-536924) |
| TGF-βRI | SD-208 |
| KIT | Imatinib mesylate (Gleevec®)*, dasatinib (Sprycel®)*nilotinib or AMN107 (Tasigna®)*, bafetinib (INNO-406) |
| Notch | γ-secretase inhibitor (DAPT, MK-0752, GSI-18) |
| Nodal/Cripto | Anti-Cripto mAb, LEFTY |
| Wnt/β-catenin | Anti-Wnt antibody, AV65, WIF-1 |
| CXCR4 | Anti-CXCR4 mAb, CXCR4 antagonist (plerixafor or AMD3100 (Mozobil®)*) |
| VEGF | Anti-VEGF mAb (bevacizumab (Avastin®)*) |
| VEGFR-2 | Anti-VEGFR-2 mAb (ramucirumab or IMC-1121B, DC101 or IMC-1C11) |
| VEGFR-2, EGFR, RET-TKI | MKI (Vandetanib or ZD6474) |
| VEGFRs, PDGFRs, KIT | MKI [Sunitinib (Sutent®)*, Axitinib or AG-013736 (Inlyta®)*] |
| VEGFR-2 and -3, PDGFRs, KIT, B-Raf, C-Raf | MKI (Sorafenib (Nexavar®)*) |
| VEGFRs, PDGFRs, FGFR-1, FGFR-3, KIT, Itk, Lck and c-Fms | MKI (Pazopanib (Votrient®)*) |
| Intracellular signalling elements | |
| HIFs | YC-1, P276-00, P3155, NSC-134754, PX-478, KCN1 G-rich ODNs (JG243 and JG244), anthracyclins, 2-methoxyestradiol, echinomycin, Rakicidin A |
| PI3K | LY294002, Wortmannin |
| mTOR | Everolimus or RAD001 (Afinitor, Zortress or Certican®)*, temsirolimus or CCI-779 (Torisel®)*, sirolimus or rapamycin (Rapamune®)* |
| PI3K/mTOR | PI-103, NVP-BEZ235 |
| Ras | S-trans trans-farnesylthiosalicylic acid |
| NF-κB | bortezomib (Velcade®)*, sulphasalazine (Azulfidine®)*, salinosporamides A (NPI-0052), parthenolide IkBα inhibitor (PS-341) |
| STAT3 | G-rich ODN (T40214) |
| COX-2 | Etodolax (Lodine SR or Eccoxolac®)*, NS-396 |
| Bcl-2 and/or Bcl-xL | AS (oblimersen sodium (Genasense®)*), ABT-263 |
| BCR-ABL | Imatinib mesylate (Gleevec®)*, dasatinib (Sprycel®)* nilotinib or AMN107 (Tasigna®)*, bafetinib (INNO-406) |
Trade name of Food and Drug Administration (FDA) approved drug for treating specific cancer(s) and/or other disorder(s).
c-Fms: transmembrane glycoprotein receptor tyrosine kinase; AS: antisense oligonucleotide; COX-2: clyooxygenase-2; CXCR4: CXC chemokine receptor 4; DAPT: N-(N-3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; EGFR: epidermal growth factor receptor; G-rich ODNs: guanine-rich oligodeoxynucleotides; FGFR: fibroblast growth factor receptor; IGF-RI: insulin-like growth factor-1 receptor; Itk: interleukin-2 receptor inducible T-cell kinase; KCN1: 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulpfonamide; Lek: leucocyte-specific protein tyrosine kinase; mAb: monoclonal antibody; MKI: multi-targeted kinase inhibitor; NF-κB: nuclear factor-kappaB; PI3K: phosphatidylinositol 3′-kinase; STAT3: signal transducer and activator of transcription 3; TGF-βR: transforming growth factor-β receptor; TKI: tyrosine kinase inhibitor; VEGF: vascular growth factor; Wnt: Wingless ligand.