Examples of currently available drugs modulating ECM metabolism beyond primary target
| Drug | Primary Mechanism of Action | Effect on ECM metabolism |
|---|---|---|
| Anti-inflammatory and immunomodulatory drugs | ||
| Corticosteroids | ||
| e.g., hydrocortisone, prednisone, dexamethasone | Various genomic and nongenomic mechanisms of action (Stahn et al., 2007) | Modulation of the expression of various types of collagen (Oikarinen et al., 1987; Russell et al., 1989; Oishi et al., 2002), elastin (Del Monaco et al., 1997), proteoglycans decorin and biglycan (Kähäri et al., 1995), HA (Saarni and Hopsu-Havu, 1978), and various noncollagenous matrix glycoproteins such as fibronectin, laminin, and tenascin (Dean et al., 1988; Simo et al., 1992; Ekblom et al., 1993); suppression of MMP synthesis and activity (DiBattista et al., 1991; Sadowski and Steinmeyer, 2001); influence on TIMP expression and activity (Sadowski and Steinmeyer, 2001) |
| NSAIDs | ||
| e.g., indomethacin, diclofenac, naproxen, and -coxibs such as celecoxib | Inhibition of cyclooxygenase enzymes -1 and -2 (Gasparini et al., 2003) | Modulation of the synthesis of fibronectin (Ernst et al., 1995), various types of collagen (Ernst et al., 1995; Liu et al., 2007), large chondroitin sulfate proteoglycans (Okada et al., 1994), and HA (Sussmann et al., 2004); suppression of MMP expression, synthesis, and activity (Sadowski and Steinmeyer, 2001; Pavlovic et al., 2006) |
| Other immunosuppressive drugs | ||
| Cyclosporine A | Calcineurin inhibitor (Ho et al., 1996) | Differential effect on collagen synthesis and fibrosis (Eickelberg et al., 2001; Fornoni et al., 2001; Waller et al., 2004); inhibition of MMP activity (Fornoni et al., 2001; Chiu et al., 2009; Saygili et al., 2009) |
| Leflunomide | Pyrimidine synthesis inhibitor (Fukushima et al., 2007) | Inhibitory effect on fibrogenesis (Yao et al., 2004; Si et al., 2007) |
| Methotrexate | Inhibitor of dihydrofolate reductase (Warren et al., 2008) | Reduction of type IV collagen synthesis and ECM expansion (Yozai et al., 2005); influence on MMP and TIMP production (Seitz and Dayer, 2000; Fiedorczyk et al., 2006). |
| Sirolimus/ rapamycin | Mammalian target of rapamycin (mTOR) inhibitor (Sehgal, 2003; Granville et al., 2006) | Blocking of the synthesis of fibrillin-1 (Schaefer et al., 2007); blocking of HA accumulation (Gouëffic et al., 2007); inhibition of growth factor induced collagen synthesis (Park et al., 2005) |
| Tacrolimus | Calcineurin inhibitor (Nghiem et al., 2002) | Suppression of cytokine stimulated MMP synthesis (Migita et al., 2005); stimulation of collagen synthesis in vascular smooth muscle cells via TGF-β signaling (Giordano et al., 2008) |
| Microbial drugs | ||
| Doxycycline | Antimicrobial drug | Inhibition of specific MMPs (Golup et al., 1998; Ahuja, 2003; Clark et al., 2008) |
| Minocycline | Antimicrobial drug | Inhibition of specific MMPs (Sutton et al., 2005; Machado et al., 2006) |
| Cytokine modulators | ||
| Etanercept | Inhibition of TNF-α receptor (Moreland, 1999) | Modulation of type II collagen synthesis and degradation (Briot et al., 2008) |
| Infliximab, adalimumab | Inhibition of TNF-α (Moreland, 1999) | Inhibition of fibrosis (Sorrentino et al., 2007); downregulation of tissue degrading MMPs (Wendling et al, 2008; Di Sabatino et al., 2009) |
| Thalidomide | Inhibitory action on TNF-α (Moreira et al., 1993) | Attenuation of fibrosis (Chong et al., 2006; Yndestad et al., 2006); influence on endostatin level (Aydoğan et al., 2007) |
| Other drugs | ||
| ACE-inhibitors | ||
| e.g., Captopril, enalapril and numerous other ones | Blocking of angiotensin converting enzyme (Johnston and Jackson, 1983) | Modulation of collagen and proteoglycan synthesis and fibrosis (Kaneto et al., 1994; Cruz et al., 2000; Wapstra et al., 2001); influence on MMPs (Rizzoni et al., 2004; Aoki et al., 2007; Okada et al., 2008) |
| ATR-blockers | ||
| e.g., Losartan and numerous other ones | Blocking of angiotensin II receptor (Gavras and Salerno, 1996) | Upregulation of thrombospondin-1 expression (Fischer et al., 2001); downregulation of fibronectin expression (Fischer et al., 2001); inhibition of CTGF and fibrosis (Rupérez et al., 2003); inhibition of specific MMPs and TIMPs (Masutomo et al., 2001; Saygili et al., 2009) |
| Calcium channel blockers | ||
| e.g., Amlodipine, felodipine, diltiazem, and verapamil | Blocking of the L-type calcium channel (Mason et al., 2003) | Inhibition of collagen expression and accumulation (Roth et al., 1996; Sugiura et al., 2000); modulation of MMP activity (Roth et al., 1996; Wada et al., 2001) |
| Calcium sensitizing drugs | ||
| e.g., Levosimendan | Calcium-sensitizer (Ng, 2004) | Reduction of MMP-2 (Tziakas et al., 2005) |
| Endothelin receptor antagonists | ||
| e.g., Bosentan | Endothelin-1 inhibitor (Motte et al., 2006) | Upregulation of MMP-9 (Giannelli et al., 2005); downregulation of fibronectin (Siddiqui et al., 2006) |
| Statins | ||
| e.g., Simvastatin, atorvastatin, and numerous other ones | Inhibition of HMG-CoA reductase (Vaughan and Gotto, 2004) | Inhibition of collagen and CTGF production (Martin et al., 2005; Rupérez et al., 2007); reduction of HA accumulation (Sakr et al., 2008); reduction of MMP-9 synthesis (Kalyanasundaram et al., 2006) |
| Tranilast | Histamine H1 receptor antagonist (Namazi and Soma, 2005) | Inhibition of collagen synthesis (Yamada et al., 1994) and accumulation (Isaji et al., 1987) |
| Tyrosine kinase inhibitors | ||
| e.g., Imatinib | Specific tyrosine kinase inhibitor (Lydon and Druker, 2004) | Blocking of the stimulation of TGF-β induced collagen gene expression (Bhattacharyya et al., 2009) |
HA, hyaluronan