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Title:   Author  item
                                            Zunino, Susanitem
                                            Storms, Daviditem
                                            Newman, Johnitem
                                            Pedersen, Theresaitem
                                            KEEN, CARL - University Of Californiaitem
                                            DUCORE, JONATHAN - University Of California
  Submitted to: International Journal of Oncology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 9/11/2012
                                    Publication  Date: 12/1/2012
                                    Citation: Zunino, S.J., Storms, D.H., Newman, J.W., Pedersen, T.L., Keen, C.L., Ducore, J.M. 2012. Dietary resveratrol does not delay engraftment, sensitize to vincristine, or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice. International Journal of Oncology. 41(6):2207-2212. DOI: 10.3892/ijo.2012.1650.Interpretive Summary: Resveratrol is present in high concentrations in red wine, and is also found in other fruits such as blueberries, mulberries, and cranberries.  Resveratrol has shown anti-cancer activity against high risk acute lymphoblastic leukemia in a cell culture system.  We investigated whether dietary supplementation with resveratrol would inhibit the growth of high risk leukemia in a mouse model for this disease.  Mice were placed on a normal control diet or a diet supplemented with 0.2% resveratrol.  Three weeks later, the mice were injected with cells that were established from a patient with high risk acute leukemia.  Resveratrol did not inhibit the growth of leukemia in these mice.  We also determined if resveratrol could make the leukemia cells sensitive to vincristine, a chemotherapeutic agent used in the clinic to treat this disease.  Comparisons of the percent of human leukemia cells in mouse blood and survival curves showed that resveratrol did not inhibit the disease or sensitize the leukemia cells to vincristine.  Analysis of resveratrol levels in the blood of the treated mice showed that resveratrol was modified by the additions of sugars and sulfur-containing molecules by the liver.  These data indicate that dietary resveratrol does not have potential as a novel preventive agent against high risk leukemia.
                                Technical Abstract: Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse.  Although resveratrol is able to kill high-risk leukemia in vitro, this agent has not been evaluated against this disease in vivo.  The efficacy of dietary resveratrol as a preventative agent against this leukemia was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL line SEM.  Five wk old mice were placed on control diet or a diet containing 0.2% w/w resveratrol.  After 3 wk on the diets, SEM cells were injected into the tail veins of all mice, and engraftment was monitored by evaluating the presence of human CD19+ cells in peripheral blood using flow cytometry.  Dietary resveratrol did not delay engraftment of the leukemia cells.  To determine if resveratrol could increase efficacy of a chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice maintained on the different diets.  Survival curves and monitoring the percent of human leukemia cells in peripheral blood showed that leukemia cell growth was not inhibited by dietary resveratrol and this dietary nutrient did not potentiate the activity of vincristine.  These data suggest that dietary resveratrol does not have potential as a novel preventative agent against the growth of high risk t(4;11) ALL in vivo.


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