Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn's disease. Regulation of MMPs is closely associated with signaling molecules, especially mitogen-activated protein kinases (MAPKs), including three representative kinases, extracellular signal regulated kinases (ERK), p38 and c-Jun N-terminal kinases (JNK). Ginseng (Panax sp.) is a plant which has been traditionally used for medicinal applications. Ginsenosides are major metabolites which have potentials to treat various human diseases. In this review, the pharmacological effects of ginsenosides have been rigorously investigated; these include anti-metastatic and anti-inflammatory activities of ginsenosides associated with suppression of MMPs via regulation of various signaling pathways. This will highlight the importance of MMPs as therapeutic targets for anti-metastatic and anti-inflammatory drug development based on ginsenosides.

Keywords: MAPK; ginsenosides; inflammation; matrix metalloproteinase; metastasis.

Figure 3

Summary of activities of ginsenoside Rg1. Structure of Rg1 and its effects on MMPs and/or signalings [61,66,67,68,70,71].

Figure 1

Backbone structures of ginsenosides. (A). Chemical structures of protopanaxatrial and protopanaxadiol, (B). Chemical structure of oleanolic acid, (C). Chemical structure of ocotillol.

Figure 2

Structure and domain organization of proMMP-2. (A) Structure of proMMP-2 is presented as an example of MMP structure. proMMP-2 is composed of functionally distinct domains. The catalytic domain, propeptide and hemopexin domain are described in orange, pink and cyan color, respectively. Zn⁺⁺ and Ca⁺⁺ ions are indicated by red and gray color, respectively. Illustration is based on the crystal structure (PDB accession number: 1CK7). (B) Domain organization of proMMP-2 is presented as a representative example of MMP domain organization.

Figure 4

Summary of activities of ginsenoside Rg3. Structure of Rg3 and its effects on MMPs and/or signalings [75,76,77,78,79,80,81,83,84,85,86,87,88].

Figure 5

Summary of activities of ginsenoside Rh1. Structure of Rh1 and its effects on MMPs and/or signalings [91,92,93,94].

Figure 6

Summary of activities of ginsenoside Rh2. Structure of Rh2 and its effects on MMPs and/or signalings [96,97,98,99,100,101,102].

Figure 7

Summary of activities of ginsenoside Rb1. Structure of Rb1 and its effects on MMPs and/or signalings [104,105,106,107].

Figure 8

Summary of activities of ginsenoside CK. Structure of CK and its effects on MMPs and/or signalings [110,111,112,113,114].

Figure 9

Summary of activities of ginsenoside Rd. Structure of Rd and its effects on MMPs and/or signalings [118,119].

Figure 10

Summary of activities of ginsenosides Rb2, F2, AD-1 and 4-XL-PPD. Structures of Rb2 (A), F2 (B), AD-1(C) and 4-XL-PPD (D) and their effects on MMPs and/or signalings [121,122,123,124].

Figure 10

Summary of activities of ginsenosides Rb2, F2, AD-1 and 4-XL-PPD. Structures of Rb2 (A), F2 (B), AD-1(C) and 4-XL-PPD (D) and their effects on MMPs and/or signalings [121,122,123,124].

Figure 11

Summary of activities of ginsenosides Rg5, Rb3, Ro and F4. Structures of Rg5 (A), Rb3 (B), Ro (C) and F4 (D) and their effects on MMPs and/or signalings [88,125,126,127].

Figure 11

Summary of activities of ginsenosides Rg5, Rb3, Ro and F4. Structures of Rg5 (A), Rb3 (B), Ro (C) and F4 (D) and their effects on MMPs and/or signalings [88,125,126,127].