# Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma
## 3 Flavonoids in Multiple Myeloma
### Epigallocatechin-Gallate  
Epigallocatechin-gallate (EGCG) is the common catechin in green tea (Figure 10) [268; 269], representing at least 50% of the total catechins in the leaves [269] and is responsible for most biological activities, including angiogenesis [270]. The anti-proliferative, pro-apoptotic, anti-invasive and anti-angiogenic properties of EGCG have been highlighted in numerous studies [271]. EGCG inhibited tumorigenesis by inhibiting carcinogenic activity [272; 273]. EGCG decreased tumor proliferation by acting against angiogenesis [274; 275; 276; 277]. EGCG inhibited tumor migration [278; 279; 280; 281] and induced tumor cell death by several mechanisms, such as lysosomal membrane permeabilization, mediated cell death, autophagy, caspase-dependent apoptosis, and caspase-independent apoptosis [268]. EGCG targeted tumor microenvironment components (e.g., fibroblasts, macrophages, fibroblasts, and microvasculature) and reduced oxidative stress, inflammation, oxidative stress, and hypoxia [282]. EGCG has acted synergistically with other natural compounds both in vitro and in vivo in various cancers (e.g., quercetin, curcumin, genistein, and caffeine) [271; 283]. Figure 10: The chemical structure of epigallocatechin-3-gallate. EGCG has been tested in combination with currently used chemotherapeutic drugs (e.g., doxorubicin, sunitinibib, and cisplatin) [284, 285, 286, 287]. In order to improve the stability and bioavailability of EGCG, new formulations were developed [288, 289, 290, 291]. Apoptosis is the main mechanisms by which EGCG exerts anticancer activity, along with cell proliferation and migration inhibition [292, 293]. EGCG affected the expression of anti-apoptotic factors (e.g., Bcl-xl, Bcl-2) and up-regulated pro-apoptotic molecules (e.g., caspase-3, Bax) in several experiments [285, 294, 295, 296]. EGCG inhibited cell growth by inducing apoptosis in MM cell lines or primary MM cells from patients [297, 298], by caspase 3 activation and Bcl-2 and Mcl-1 reduction. Additionally, it induced loss of mitochondrial transmembrane potential and intracellular H\({}_{2}\)O\({}_{2}\) and superoxide increasing [298]. EGCG-mediated apoptosis was the result of a direct interaction with 67 LR laminin receptor and lipid-shelf clustering, which correlated with increased activation of sphingomyelinase acid (ASM) via protein kinase C delta (PKC8). This has been demonstrated both in vitro in U266 cells and in cells harvested from patients with MM [299, 300] and in vivo [297, 300]. EGCG inhibited proliferation and induced apoptosis in U266 cells, a phenomena that was accompanied by the inhibition of the expression enhancer of homologous zest 2 (EZH2) [301], EGCG activated caspase-3, -8, cleaved caspase-9, and PARP and subsequent apoptosis [302]. EGCG has been used in MM clinical practice in combination with phosphodiesterase 5 inhibitor varadenafil [299] or in vitro, together with L-Threo-dihydroosphingosine in vitro [303], and hydrogen sulphide donors [304]. Thus, an attempt was made to reduce the dose of EGCG and hepatic adverse effects [305, 306, 307, 308] and to improve the anti-hepatic effects. MM ale EGCG [299, 303, 304]. [PERSON] et al. [309] reported that cyclic guanosine monophosphate (cGMP) induced by EGCG activated the PKC8/ASM singling axis in MM cells. Induction of cGMP was sufficient to induce phosphorylation of PKC8 at Ser664, the major kinase for the induction of ASM activation by EGCG. The inhibitors of the negative regulators of diacylglycerolcerol (DAG) increased the effect of EGCG. EGCG treatment increased phospholipase C (PLC) activity. EGCG-induced ASM activation was completely suppressed by PLC inhibition. Thus, EGCG-induced cGMP activated the cGMP/PLC/PKC8/ASM signaling axis in MM cells.