# Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma
## 2 Molecular Pathways Involved in Multiple Myeloma Progression  
Numerous signaling pathways (WNT, RANK/RANKL/OPG, RAS/MAPK, PI3K/Akt/mTOR, JAK/STAT3, NF-kB) are involved in MM, as well as extracellular mediators (TNF\(\alpha\), IL8, TGF\(\beta\)1, (IL6, FGF-2, PDGF, IGF, VEGF) [60].  
Mitochondrial-mediated apoptosis is an important apoptotic pathway, influenced by pro-apoptotic factors, such as cleaved-caspase-3 and -9, and Bcl-2 family [61]. Bcl-2 family proteins (Bax, Bad, and Bcl-2) are the major regulators of apoptotic processes and play a key role in mitochondrial-mediated apoptosis [62; 63].  
Activation of Bcl-2 pathways may regulate mitochondrial-mediated apoptosis. Interactions between Bcl-2 proteins can regulate permeabilization of the outer mitochondrial membrane by cytoplasmic releasing of cytochrome C, and plays a critical role in activation of the apoptosis-inherited pathway [64; 65]. Moreover, Bax, Bad and Bcl-xs, may facilitate the releasing of cytochrome C or may inhibit anti-apoptotic proteins [66].  
Inhibition of the PI3K/Akt/mTOR signaling pathway is crucial for the antiproliferative effect on MM cells [67; 68]. Akt is the main downstream target of PI3K [69]. Inhibition of PI3K/Akt/mTOR is beneficial for improving the life quality of MM patients [70]. Phosphorylated Akt binds to PI3K-activated products, and inhibit the pro-apoptotic factors of caspase-3, -9, and Bad [71]. Moreover, MTOR is a significant downstream target of Akt [72].  
STAT3 is a transcription factor that may be overexpressed in multiple myeloma. It correlates with enhanced proliferation and apoptosis resistance to therapy. STAT3 activation negatively regulated the T cell-mediated immune response [60]. Aberrant signal transducer activation and transcriptional activator 3 (STAT3) is a key event of the cancerogenesis by inducing anti-apoptosis, angiogenesis, invasion, and metastasis [73; 74; 75; 76]. STAT3 has been shown to be constitutively active in approximately 40 to 60% of MM tumors [77; 78; 79; 80; 81].  
Decreased expression of different IL6/JAK/STAT signaling pathways by epigenetic silencing may sensitize MM cells to IL-6-regulated proliferation and survival [77; 78; 82].  
Activated STAT3 induced transcription of target genes leads to increased survival, proliferation and drug resistance of MM cells: Src homology containing protein 1 (SHP-1), suppressor of cytokine signaling 1 (SOCS1), estrogen receptor (ER), Janus Associated kinase (JAK), phosphatase of regenerating liver 3 (PRL3), and peroxisome proliferator activated receptors (PPAR) [83].  
Abnormal activation of the Wnt signaling mediate MM cells proliferation, survival, and drug resistance [84; 85; 86]. \(\beta\)-catenin is an essential component of the canonical Wnt pathway regulation [87; 88]. B-catenin activity is strictly controlled by several processes,such as ligand-receptor interactionsprotein stability, nuclear translocation, protein stability, and transcriptional activity [89; 90; 91].  
Nuclear factor kappa B (NF-\(\kappa\)B) is an important transcription factor involved in the proliferation and MM cells survival. NF-\(\kappa\)B regulates the activation of various molecules involved in apoptosis, as anti-apoptotic proteins or X-linked inhibitor of apoptosis protein). XIAP is the most studied protein that inhibits apoptosis and negatively regulates caspases in MM [92].  
Mitogen-activated protein kinase (MAPK) is a cell survival regulator, and Jun N-terminal kinase (JNK) signaling is a component of this pathway. PARP14 is overexpressed in over 80% of MM cells and is regulated by JNK2 [93].  
The best strategy for the treatment of MM is a single agent or combination of molecules targeting several dysregulated signaling pathways.