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Bethany LaVergne and Curt Phifer, Ph.D. at Northwestern State University Fabiola Gomez, Ph.D. and Varsha Gandhi, Ph.D.; MD Anderson Cancer Center
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“A disease in which abnormal cells divide without control and can invade nearby tissues” (NCI dictionary) Enhanced survival mechanisms difficult to kill cancer cells Physical, emotional, and financial impact Prevention and treatment protocols for many cancers are available
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Leukemia = cancer of the blood Lymphocytic = B-lymphocytes Chronic = slow, gradual development Patients are 60-80 years old; rarely under 40 Complications with immune system Family history is good predictor of risk Elevated levels of Bcl- 2 and Pim kinase
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ABT- 737 (Abbot Labs) binds to and sequesters Bcl- 2 AZD- 1208 (Astra Zeneca) inhibits Pim kinase function
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Blood samples were obtained from 7 CLL patients and 1 healthy blood donor Mononuclear cells (including B-lymphocytes) were isolated from blood Each sample was treated 24 hours total Cell death determined by Annexin V/Propidium iodide staining Additive, Antagonistic, and Synergistic
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1 nm was used in combination treatments 3 μM and 10 μM AZD- 1208 were determined sufficient by a similar experiment
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1 nM ABT- 737 3 μM AZD- 1208 10 μM AZD- 1208 1 nM ABT- 737 + 3 μM AZD- 1208 1 nM ABT- 737 + 10 μM AZD- 1208
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1 nM ABT- 737 3 μM AZD- 1208 10 μM AZD- 1208 1 nM ABT- 737 + 3 μM AZD- 1208 1 nM ABT- 737 + 10 μM AZD- 1208 No treatment DMSO
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Variation between samples Additive results at best Highest % cell death induced: 40% from 1 nM ABT- 737 + 10 μM AZD- 1208
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Kang, M, Reynolds, C. “Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy.” Clinical Cancer Research 2009, 15: 1126-1132. Martinou, J, Youle, R. “Mitochondria in Apoptosis: Bcl-2 Family Members and Mitochondrial Dynamics.” Developmental Cell 2011, 21: 92-101. Nawijn, M, Alendar, A. Berns, A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nature Reviews 2011, 72: 23-34. Perez, K, Winer, E. “Chronic Lymphocytic Leukemia: Something Old, Something New and Something Borrowed…” Rhode Island Medicine and Health 2011, 94: 15- 18. Reed, J, Pellecchia, M. Apoptosis-based therapies for hematologic malignancies. Blood 2005, 106: 408-416. Song, J, Kraft, A. Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737. Cancer Research 2012, 72: 294-303.
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