# Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma
## 3 Flavonoids in Multiple Myeloma
### Wogonin  
Wogonin is one of the active mono-flavones extracted from the root of the _Scutellaria baiaclensis_ (Figure 6) [124; 183].  
It has neuroprotective [184; 185], anti-inflammatory, and anti-cancer activity [186; 187; 188; 189; 190; 191; 192]. Wogonin has been shown to induce cytotoxicity to cancer cells in vitro and inhibited tumoral growth in vivo [124; 183].  
Wogonin targets several signaling pathways to prevent and inhibit the development of cancer both in vitro and in vivo [193; 194]. Wogonin is involved in several anti-proliferative processes mediated by ER stress, MAPK, ROS, inhibition of transcription factors, such as NF-kB or activator protein-1 (AP-1), and intracellular suppression Ca\({}^{2+}\) signaling [124; 194]. Due to its therapeutic potential and a lower toxicity to normal cells [183], this bioactive compound is an adjuvant in chemotherapy by increasing the therapeutic effects and reducing the side effects of conventional drugs [195].  
Because MM-induced angiogenesis is an essential process for cancer progression and metastasis, methods of inhibiting angiogenesis have been studied as a new anti-myeloma treatment [196; 197]. [PERSON] et al. [198] showed that wogonin inhibited MM-induced angiogenesis in both normoxic and hypoxic conditions by reducing the secretion of proangiogenic factors (VEGF, PDGF and bFGF) in U266 and RPMI 8226 cells and in co-cultures of MM and stromal cells. The antiangiogenic effect of wogonin was previously reported by [PERSON] et al. [199] in MCF-7 breast cancer cells.  
The c-Myc/HIF-1\(\alpha\) plays an essential role in activation of different pro-angiogenic factors (e.g., PDGF, VEGF, and bFGF) [200]. Wogonin induced c-Myc inhibition and stimulated HIF-1\(\alpha\) degradation in vitro. This biologically active compound has the ability to inhibit in vivo tumor angiogenesis and growth in an experimental model of BALB/c- nude mice. Wogonin showed synergistic action against MM-dependent angiogenesis in combination with lenalidomide and bortezomib and inhibited expression of c-Myc and HIF-1\(\alpha\) in primary MM cells [198].  
[PERSON] et al. [201] reported a cytotoxic effect of wogonin in vitro, as demonstrated by the induction of apoptosis on RPMI8226 cells. Wogonin blocked the cells in the sub-G1 phase. Poly ADP ribose polymerase (PARP) has an important role in mediating the normal cellular response to DNA damage, and enzymatic cleavage is considered to be a marker of apoptosis. Wogonin inhibited PARP in a dose-dependent manner and induced PARP cleavage. Moreover, wogonin increased Bax expression in MM cells, suggesting its ability to stimulate apoptosis via Bax-regulating pathway. Besides, Bcl-2 expression was reduced following wogonin treatment. Wogonin inhibited Akt phosphorylation (Ser 473) in MM cells, the latter being a key event in tumorigenesis and apoptosis. Wogonin treatment did  
Figure 6: The chemical structure of wogonin.  
not alter the total Akt protein level. This study suggests that wogonin-induced MM cell apoptosis could be modulated by the Akt pathway, because residual phosphorylation at Ser 473 is required for Akt activation [202].