Abstract 3318: Exploring the utility of natural and synthetic resveratrol derivatives for bone regrowth following loss due to breast cancer therapies

Many of the most widely used therapies for the treatment of breast cancer have been associated with enhanced rate of bone loss, including chemotherapies and hormone therapies, due to alteration of normal hormone signaling. Bone loss is due to a shift in the balance between osteoblast and osteoclast cells that are derived from a common precursor, mesenchymal stem cells (MSC), found in the bone marrow. Estrogen is an important mediator of both hormone-responsive breast cancers and normal bone development and regeneration, favoring MSC differentiation down the osteoblast lineage. Stilbenes, defense compounds produced by plants including red grapes, peanuts, and blueberries, have been popularized in recent years based on observed health benefits. Resveratrol, the most widely studied stilbene, has been credited with many health benefits including cardiovascular health, anti-cancer and antioxidant effects, and inhibition of obesity and diabetes. Many stilbenes, including resveratrol can be classified as phytoestrogens due to their ability to bind and alter the activity of the estrogen receptor. A series of 28 stilbene compounds, including resveratrol and pterostilbene, were obtained by the U.S. Department of Agriculture and screened for effects on MSC differentiation. MSC were treated with stilbene compounds (both E and Z isoforms) and cultured in either osteogenic or adipogenic differentiation media for 7-21 days. Following differentiation, cells were stained with (1) Alizarin Red S to identify calcium deposits or (2) Oil Red O to identify lipid droplets. Several compounds were found to stimulate osteogenesis while inhibiting adipogenesis and were selected for further study and development. Realtime PCR for known genes associated with osteogenesis (ALPL, RUNX2, OCN, OPN) and adipogenesis (ADIPOQ, GLUT4, LEP, PPARG) were used to confirm differentiation and gain insight into the mechanism of altered differentiation. Unlike estrogen, stilbenes do not appear to negatively impact breast and reproductive organs. Stilbenes thus represent a novel option for inducing a preferential shift of MSCs toward the osteogenic lineage while potentially avoiding the negative health effects of estrogen. Targeting the differentiation of MSC to favor bone formation represents a viable target for the development of novel therapeutics for bone loss following cancer treatment. Further, identifying compounds that stimulate osteogenesis while repressing adipogenesis could benefit other me