# Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma
## 3 Flavonoids in Multiple Myeloma
### Quercetin  
Quercetin is one of the most important bioflavonoids found in over 20 plants [244], such as berries (blueberries and cranberries), apples, green leafy vegetables, onions, broccoli, cauliflower, cabbage, as well as nuts and seeds [244; 245]. It contains two benzene rings joined through a 3-carbon heterocyclic pyrone one (Figure 9). Due to the presence in the structure of quercetin of two antioxidant pharmacophores, it has the ability to easily neutralize free radicals and can bind to metal ions. Catechol with OH group present in the C3 position is an ideal structure that favors the free radical neutralization [246].  
The quercetin name derives from the Latin word \"Quercetin\", which means oak forest [247]. The name of the International Union of Pure and Applied Chemistry (IUPAC) of quercetin is 2- (3,4-dihydroxyphenyl) -3,5,7-trihydroxychromen-4-one [245].  
Quercetin belongs to the flavonoids and is not being produced by the body [247]. It is soluble in lipids and alcohol, insoluble in cold water and has a lower solubility in hot water [244; 245].  
Quercetin is available as a supplement and can be safely orally administrated at a dose of 1 g/ day and absorbed up to 60% [248].  
Quercetin exhibits many pharmacological activities, such as antioxidant, anti-inflammatory, anti-diabetic, and anti-proliferative activity [246; 249]. The anticancer properties of quercetin have been highlighted in numerous studies [250; 251; 252], as evidenced by the antioxidant,  
Figure 8: The chemical structure of myricetin.  
Figure 9: The chemical structure of quercetin.  
antiproliferative and growth factor inhibition effect deletion [253]. This flavonoid has had the ability to inhibit various cancers, such as breast cancer [254], lung [255], pancreatic [256], colorectal [257], prostate [258], ovarian cancer [259], nasopharyngeal [260], and kidney [261].  
Quercetin increased the sensitivity of tumor cells to doxorubicin [262; 246], vincristine [263], and 5-fluorouracilacil [264].  
[PERSON] et al. [265] studied the effect of quercetin on multiple myeloma cell line NCI-H929. Quercetin inhibited cell proliferation, stimulated apoptosis and induced cell cycle blockade in G2/M phase. Quercetin activated caspase-3, -8, -9, and PARP apoptosis-associated proteins and inhibited BCL-2 expression. It also stimulated P21, P53, and P27 expression and inhibited CDK4 expression in NCI-H929 cells. Quercetin decreased the p-ERK and p-AKT phosphorylation in NCI-H929 cells.  
[PERSON] et al. [266] demonstrated that quercetin inhibited proliferation in ARP-1, RPMI8226, and MM.1R cell lines by inducing apoptosis and blocking the cell cycle in the G2/M phase. Quercetin upregulated caspase-3, -9, PARP, p21 and downregulated c-myc. The combination of quercetin with dexamethasone showed in vitro and in vivo synergistic inhibitory effect, stimulated apoptosis of MM cells and induced caspase-3 activation. Quercetin also inhibited in vivo tumor growth in vivo (ARP-1 cells in NOD-SCID mouse model).  
Quercetin inhibited MM cell proliferation by downregulating the expression of IQ motif-containing GTPase activating protein 1 (IQGAP1) and the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Quercetin also inhibited activation of MAPK and the interaction between IQGAP1 and ERK1/2 in MM cells [267].