Table 1.
Molecular targets and pharmacologic modulators for cellular microenvironment
| Signaling Pathway/ Molecular Target |
Agent(s) | Effect on target | Cancer cell type involved (in vivo or cell line) |
|---|---|---|---|
| INFLAMMATION | |||
| NFKB | N-acetyl cysteine, Resveratrol, Sutinib | Inhibitory [1–3] | RCC, GIST [4, 5] |
| COX1/2 | Celecoxib, Aspirin, other NSAIDs | Inhibitory [6, 7] | Colon polyp recurrence, Breast, Oesophageal, Gastric, Biliary [8, 9] |
| NOS | L-NAME | Inhibitory [10] | Breast [10] |
| AP1 signaling | PYC71N, JIP peptide, Resveratrol | Inhibitory [2, 11, 12] | Breast [13] |
| NRF2 | Sulphoraphane, Dimethyl fumarate | Activation [14] | Prostate [15] |
| NRF2 | Brusatol | Inhibitory [16] | Lung [16] |
| MMPs | Marimastat, MMP3 inhibitor peptide | Inhibitory [17, 18] | Lung, Colon [17, 19] |
| TGF β signaling | AP12009, LY 364947, SB 525334 | Inhibitory [20–22] | Prostate, Glioma [23, 24] |
| SENESCENCE | |||
| Notch/CSL | SAHM1, MK0752, RO4949079 | Inhibitory [25, 26] | Breast, Prostate [24, 27] |
| p21 | Senexin A | Inhibitory [28] | Adenocarcinoma [28] |
| MEK | Trametenib, PD035901, UO126, Pimasertib | Inhibitory [29–31] | Melanoma, Lung, Colon [32–34] |
| AUTOPHAGY | |||
| mTORC complex | Rapamycin, Torin, CCI-779, RAD001, AP23573 | Activation [30, 35] | Glioma, Prostate, RCC [24, 36, 37] |
| AMPK | Metformin, AICAR, A-769662 | Activation [30, 38] | Breast, Colon [39, 40] |
| BH3 | ABT 737, GX15-070 | Activation [41, 42] | Pancreas, Leukemia [43, 44] |
| HDAC | Sperimidine, Apicidin, SAHA, Sulphoraphane | Activation [14, 45, 46] | Breast, CML [47–49] |
| Autophagosome/ly sosome | Bafilomycin A1, Chloroquine | Inhibitory [50, 51] | Breast, Prostate, Glioma [47, 52, 53] |
| Vps34, PI3Kγ | 3-methyl-adenine | Inhibitory [50, 51] | Colon, Breast [54, 55] |
• This Table indicates potential molecules that might be targeted in the stroma for cancer preventive-therapeutic purposes as well as some type of cancers or cell lines where certain indicated drugs have been found to be effective, and is not meant to be a comprehensive list of inhibitors/activators.
• Note that some agents directly target the indicated molecules while others act modulating the pathway leading to the molecular target.
List of abbreviation used:
EGCG (epigallocatechin-3-gallate); Celecoxib (sulfonamide nonsteroidal anti-inflammatory drug, NSAID); NSAIDs (non-steroidal anti-inflammatory drugs); AICAR (5-amino-1-β-ribofuranosylimidazole-4-carboxamide); Vps34 (phosphatylinositol 3-kinase class III); PI3Kγ (phosphoinositide 3-kinase gamma ); Senexin A (inhibitors of p21-dependent transcription); Resveratrol (3,5,4'-trihydroxy-trans-stilbene); Sutinib (targets multiple receptor tyrosine kinases. Including all receptors for platelet-derived growth factor (PDGF-Rs) and vascular endothelial growth factor receptors); L-NAME (N-nitro-L-arginine methyl ester); Sulphoraphane (1-Isothiocyanato-4-methylsulfinylbutane, polyvalent molecule derived from vegetables, activates NRF2); SAHM1 (hydrocarbon-stapled peptides that disrupt a critical protein-protein interaction in the Notch/CSL transcription factor complex); Marimastat (BB2516, broad spectrum MMP inhibitor); Torin (mTOR kinase activity inhibitor); CCI-779, RAD001 and AP23573 (mTOR inhibitors analog to rapamycin); Brusatol (selectively inhibits NRF2 ); JIP (Jun interacting protein1); MMP3 inhibitor I (Ac-Arg-Cys-Gly-Val-Pro-Asp); Spermidine (polyamine compound, HDAC inhibitor)
COX2 (cyclooxygenase 2); TGFβ (transforming growth factor-β); mTOR (mammalian target of rapamycin); AMPK (AMP activated kinase); MEK (mitogen-activated protein kinase); MMPs (metalloproteinase); AP1 (activating complex protein 1); NFκB (nuclear factor κB); HDAC (histone deacetylase); KEAP1 (kelch-like ECH-associated protein 1); p21 (cyclin dependent inhibitor waf1); HDAC (Histone deacetylases ); BH3 (bcl2 homology domain 3); CML (chronic myeloid leukemia); RCC (renal cell carcinoma); GIST (gastrointestinal stromal tumors)
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