# Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma
## 3 Flavonoids in Multiple Myeloma
### Fisetin  
Fisetin is a bioactive flavonoid that has a diphenylpropane structure [203] containing two aromatic rings bounded by a three carbons and supplemented with four hydroxyl group substitutions and one oxo group [204,205] (Figure 7).  
Fisetin is synthesized in strawberries, apples, cucumbers, and onions [206] or plants such as _Acacia berlandieri_, _Acacia greggit_, _Gleditschia triacanthow_, and _Rhus cotinus_[207]. The average daily intake of insertion is estimated to be about 0.4 mg in humans [208]. This potent bioactive phytoconstituent acts as a coloring agent in plants [206].  
Fisetin has low water solubility and poor intestinal absorption and therefore has low bioavailability [209,210]. Its solubility and bioavailability can be improved by complexing it with cyclodext, encapsulating with nanoparticles [211,212,213] and cocrystallization with caffeine, isonicotinamide and nicotinamide [214,215]. These changes aim to improve stability, solubility and biological effects of fisetin. The biological activity of fisetin depends on the presence of hydroxyl and oxo groups. Hydroxyl groups at C-7 and the double bond C2-C3 are essential for its antioxidant activity [216,217].  
Fisetin showed antioxidant [218], anti-angiogenic [219,220,221], anti-proliferative [222,223], anti-inflammatory [208,224], anti-aging [225], and antitumor properties [226,227].  
Fisetin induced apoptosis, cell cycle blocking and inhibition of CDK activity in various human cancer cell lines. It has also modulated lipid kinase and protein kinase pathways [228,229,230]. The anticancer activity of fisetin has been highlighted by its involvement in various signaling pathways, as blocking the mammalian target of rapamycin (PI3K/Akt/mTOR)/phosphatidylitol-3-kinase/protein kinase B, mitogen-activated protein kinases)-dependent nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and p38 [231,232].  
[PERSON] et al. [207] reported that fisetin showed cytotoxic effect and induced apoptosis in U266 cells and blocked the cell cycle in sub-G1 phase. Additionally, it improved the PARP cleavage. Fisetin inhibited the expression of anti-apoptotic Bcl-2 and Mcl-1L, but not Bcl-xL, and increased the expression of pro-apoptotic Bax, Bim and Bad.  
AMP-activated protein kinase (AMPK) plays an important role in inducing apoptosis [233,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,252,254,256,257,258,259,253,254,257,258,259,256,259,257,258,259,259,250,251,252,2  
Myricetin has various pharmacological activities, such as antioxidant, anti-inflammatory, analgesic, antitumor, hepatoprotective, and antidiabetic activity [238].  
The anti-cancer activity of myricetin was confirmed by a number of in vitro and in vivo cytotoxicity studies. Miricetin acted as an antioxidant, antimetastatic, immunomodulatory agent, apoptosis inducer, inhibitor of angiogenesis, and proliferation and growth promoter [238].  
Myricetin induced apoptosis in different cell lines, including colon, pancreatic, esophageal, ovarian, or hepatoma carcinoma cells [239; 240; 241; 242].  
[PERSON] et al. [243] showed that bulk and nano forms of mycetin showed an insignificant genotoxicity level in the lymphocytes of MM patients compared to those of healthy ones. This effect was induced by altering the Bcl-2 expressions. The Bcl-2/Bax ratio decreased and the level of P53 protein increased in the lymphocytes of MM patients. Myricetin bulk and nano-treatment induced an increase in intracellular ROS levels, suggesting that modulation of apoptotic proteins triggered by myricetin occurs through P53 and oxidative stress-dependent pathways.