The response of acute myeloid leukemia (AML) cells to small molecule inhibitors that target p53, Akt and Bcl-2 / Negin Misaghian.
| Author/creator | Misaghian, Negin author. |
| Other author | McCubrey, James A., degree supervisor. |
| Other author | East Carolina University. Department of Biology. |
| Format | Theses and dissertations |
| Production | 2008. |
| Description | 57 leaves : illustrations ; 29 cm |
| Supplemental Content | Access via ScholarShip |
| Subjects |
| Summary | The current treatment of Acute Myeloid Leukemia(AML) consists of a combination treatment of chemotherapy drugs, which primarily work by inhibiting cellular proliferation. This treatment, while efficacious initially, often decreases in effectiveness and eventually leads to drug resistance, leading to poor long-term survival for patients. Small molecule inhibitors show an alternative approach to treating AML because they can be used to target specific proteins within two of the main cell-signaling pathways associated with AML without knowing the exact mutation. By targeting specific proteins, apoptosis can be enhanced and proliferation inhibited. The three whose response to specific small molecule inhibitors was studied were the p53, Akt and Bcl-2 proteins. The effect of MDM2, P13K and Bcl-2 inhibitors was studied on these three proteins using the Molm-13 cell line in combination with retroviral vectors of interest. With regards to Bcl-2, its activity was found to be increased in Molm-13 doxorubicin resistant cells as compared to Molm-13 cells alone. Using both Molm-13 and Molm-13+p53 DN cell lines, a small, yet consistent synergistic effect was observed when the Bcl-2 inhibitor was combined with doxorubicin. This was demonstrated using both proliferation assays and staining used to highlight the apoptotic response. In the case of Akt, Molm-13+ Akt active and Molm-13+ Akt kinase dead cell lines were used in addition to just Molm-13and Molm-13+ p53 DN. In this case, the Molm-13 was the most responsive while the Molm-134- p53 DN least response to combination treatments. However, both Molm-13+ Akt active and Molm-13+ Akt kinase dead cell lines had similar responses, shown both in AO/EB staining and MTT data. While varied in the extent of the response, all 4 cell lines demonstrated a significant synergistic effect in response to combination treatments of doxorubicin with the PI3K inhibitor. Finally, an MDM2 inhibitor was used to study the response of the pro-apoptotic, p53 protein. As expected, the Molm-13 was much more response to doxorubicin alone and particularly to combination treatment in comparison to the Molm-13+p53 DN cell line. This effect was observed in AO/EB staining, MTT proliferation analysis and western blotting. |
| General note | Presented to the faculty of the Department of Biology. |
| General note | Advisor: James A. McCubrey |
| Dissertation note | M.S. East Carolina University 2008 |
| Bibliography note | Includes bibliographical references (leaves 54-57). |
| Genre/form | Academic theses. |
| Genre/form | Academic theses. |
| Genre/form | Thèses et écrits académiques. |