Syringetin

Oncology Reports, 2015.

Syringetin suppresses osteoclastogenesis mediated by osteoblasts in human lung adenocarcinoma.[Reference: WebLink]

Bone metastasis in lung cancer results in an unfavorable outcome for patients by not only impairing the quality of life, yet also increasing the cancer-related death rates.
METHODS AND RESULTS:
In the present study, we discuss a novel treatment strategy that may benefit these patients. Human CD14+ monocytes treated with macrophage-colony stimulating factor (M-CSF)/receptor activator of nuclear factor κB ligand (RANKL) differentiated into osteoclasts, whereas Syringetin (SGN), a flavonoid derivative found in both grapes and wine, suppressed the osteoclastogenesis in vitro in a dose‑dependent manner. In addition, SGN inhibited osteoclast formation induced by human lung adenocarcinoma A549 and CL1-5 cells. The associated signaling transduction pathway in osteoclastogenesis and SGN inhibition was found to be via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. Blocking AKT and mTOR by respective inhibitors significantly decreased lung adenocarcinoma-mediated osteoclastogenesis. Moreover, SGN regulated the lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts by suppressing the stimulatory effect of lung adenocarcinoma on M-CSF and RANKL production in osteoblasts, and reversing the inhibitory effect of the lung adenocarcinoma on OPG production in osteoblasts. The present study has two novel findings. It is the first to illustrate lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts, leading to osteolytic bone metastasis. It also reveals that SGN, a flavonoid derivative, directly inhibits osteoclastogenesis and reverses lung adenocarcinoma‑mediated osteoclastogenesis.
CONCLUSIONS:
In conclusion, the present study suggests that SGN, a natural compound, prevents and treats bone metastasis in patients with lung cancer.

Molecular Nutrition & Food Research, 2009, 53(11):1452-1461.

Syringetin, a flavonoid derivative in grape and wine, induces human osteoblast differentiation through bone morphogenetic protein-2/extracellular signal-regulated kinase 1/2 pathway.[Reference: WebLink]

Syringetin (3,5,7,4'-tetrahydroxy-3',5'dimethoxyflavone), a flavonoid derivative, is present in grape and wine.
METHODS AND RESULTS:
By means of alkaline phosphatase (ALP) activity, osteocalcin, and type I collagen ELISA, we have shown that Syringetin exhibits a significant induction of differentiation in MC3T3-E1 mouse calvaria osteoblasts and human fetal osteoblastic 1.19 cell line human osteoblasts. ALP and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively. Our results indicate that Syringetin stimulates osteoblast differentiation at various stages, from maturation to terminally differentiated osteoblasts. Induction of differentiation by Syringetin is associated with increased bone morphogenetic protein-2 (BMP-2) production. The BMP-2 antagonist noggin blocked Syringetin-mediated ALP activity and osteocalcin secretion enhancement, indicating that BMP-2 production is required in Syringetin-mediated osteoblast maturation and differentiation. Induction of differentiation by Syringetin is associated with increased activation of SMAD1/5/8 and extracellular signal-regulated kinase 1/2 (ERK1/2). Cotreatment of ERK1/2 inhibitor 2'-amino-3'-methoxyflavone inhibited Syringetin-mediated ALP upregulation and osteocalcin production.
CONCLUSIONS:
In conclusion, Syringetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and ERK1/2, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass.