Room C211, College Building, Middlesex University, The Burroughs, London NW4 4BT
There are several genetic mutations identified in AML patients with FLT3 mutation being one of the most frequently observed mutation which results in poor treatment prognosis. The loss of autoinhibition due to FLT3 mutation promote survival and proliferation of AML cells. FLT3 is a key driver of AML and its mutation is also linked to high risk of relapse even after bone marrow transplant. This is due to the involvement of FLT3 kinase in the early stages of blood cell production. FLT3 inhibitors have been evaluated in clinical trials leading to the approval of Midostaurin for the treatment of FLT3 mutation. However, drug resistance and kinase selectivity are challenges faced by current FLT3 inhibitors. The aim of this study was to investigate the anti-leukaemic effect of α-mangostin, singly and in combination with doxorubicin (Dox) in the relapsed AML cell line MOLM-13 with FLT3 mutation. The results showed that α-mangostin at 5-50 µM inhibited MOLM-13 cell growth in a dose-dependent manner. α-Mangostin also showed synergistic effect in reducing cell viability when combined with Dox. More apoptotic effect was observed with the combined drug, with more TUNEL positive cells and increased expression of the pro-apoptotic protein Bak (p<0.05) compared to Dox treatment alone. Furthermore, combination of α-mangostin and Dox blocked MOLM-13 cell cycle at G2/M phase by activating p53 and p21. In addition, an increased p16 expression was demonstrated with the combined drug suggesting possible senescence. However, the differences in the effect of the combined drug compared to Dox alone for the G2/M arrest, p53, p21 and p16 were not shown to be statistically significant (p>0.05) and hence caution is exercised in the interpretation of the results. Nevertheless, the combined drug suppressed phosphorylation of FLT3-ITD and cdc25 phosphatases with statistically significant (p<0.05) results when compared to Dox only. Therefore, further studies are warranted to confirm the effects of the combined drug used as a potential FLT3 inhibitors.