The long-term goal of these studies is to determine whether resveratrol and curcumin can be useful as novel therapeutic agents to increase survival of individuals with high-risk leukemia with t(4;11) translocation.
The specific aims are to determine if these agents can kill this leukemia and inhibit relapse, and to analyze the mechanistic actions in vivo. Non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice will be engrafted with leukemic cells by tail vein injection. Engraftment will be positively established when the proportion of human leukemia cells in the peripheral blood reaches 1%, as determined by flow cytometric analysis using anti-human CD19 and CD13. Both the SEM cell line and underived leukemic cells from patients with t(4;11) leukemia will be used. Chemotherapeutic efficacy will be determined by treating leukemic mice intraperitoneally with vehicle, vincristine (positive control), resveratrol (40 mg/kg body weight daily for 28 days), or curcumin (100 mg/kg body weight daily for 28 days). Inhibition of relapse will be tested by treating leukemic mice with the chemotherapeutic agent vincristine and then feeding the mice diets containing either 0.2% w/w resveratrol or 0.5% w/w curcumin. Minimal residual disease and re-engraftment will be monitored by PCR and flow cytometry, respectively. Sixteen mice will be used in each group. Efficacy of resveratrol and curcumin in the prevention and treatment of leukemia will be measured in all experiments by length of survival of the mice compared to negative control animals and results from post-mortem autopsy of bone marrow, blood, spleen, and liver. Survival data will be analyzed by Kaplan-Meier survival curves and differences between curves evaluated with the log-rank test. Cell cycle, caspase activation, Bcl-2 levels, and mitochondrial membrane depolarization will be analyzed in the leukemic cells by flow cytometry to determine in vivo mechanisms of cell death induced by resveratrol and curcumin. High-risk leukemias have a very poor survival rate due to resistance developed against currently used therapeutic drugs, which makes it necessary to find better approaches for treating this disease. These studies will provide information about whether the plant antioxidants resveratrol and curcumin may be novel and efficient alternatives for the treatment of high-risk leukemia. ? ? ?
|Zunino, Susan J; Storms, David H; Newman, John W et al. (2013) Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD/SCID mouse model. Int J Oncol 42:741-8|
|Zunino, Susan J; Storms, David H; Newman, John W et al. (2012) Dietary resveratrol does not delay engraftment, sensitize to vincristine or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice. Int J Oncol 41:2207-12|
|Zunino, Susan J; Storms, David H; Newman, John W et al. (2012) Resveratrol given intraperitoneally does not inhibit the growth of high-risk t(4;11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model. Int J Oncol 40:1277-84|
|Zunino, Susan J; Storms, David H; Ducore, Jonathan M (2010) Novel in vivo model of inducible multi-drug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11). Cancer Lett 296:49-54|