Investigating the Role of Antibiotic in Acute Myeloid Leukemia

Abstract

Background: Acute Myeloid Leukemia (AML) is the abnormal proliferation of white blood cells that are still developing from myeloid stem cells. It is incredibly heterogeneous and has many subtypes based on the many translocations associated with it. One of its subtypes, the t (6,9) AML makes up only 1% of all AMLs. AML subtype with t (6,9) is rare, has early onset, is extremely aggressive and has poor prognosis. There is no specified targeted therapy for t (6,9) AML, which is particularly resistant to chemotherapy as well. Gramicidin A is an antibiotic and recently has been reported to inhibit tumorigenesis in solid cancers. Our preliminary studies also showed its toxic effect on cell lines for myeloid leukemia. However, the exact molecular mechanisms responsible for inhibiting cancer growth have not been explored to establish it as a therapeutic agent for both solid and liquid tumors. Aim: Our aim is to investigate its effects on FKH-1 cell line specific to t (6,9) AML and U937 as control via in-silico and in vitro approaches. Methodology: Molecular Docking of FKH1 and U937 cell line targets with ligand (Gramicidin A) was performed using PyRx to find targets for the drug. Proteins with the lowest binding energies were selected for further molecular analysis and modeling via Discovery Studio Visualizer. The Insilco data presented promising binding targets, particularly with the NUP214 domain of the oncofusion protein DEK-NUP214. The antiproliferative potential of Gramicidin A was observed through MTT assay and further validated through RT-PCR. Conclusion: Interestingly, it was found that the drug Gramicidin A aggressively promotes growth in FKH-1 cell lines, while inhibiting cell growth in U-937, K-562, and Nb4 cell lines. The IC-50 value was achieved at drug concentration as low as 0.25 μM. Conclusively, these results suggest a favorable role of gramicidin A as a potent inhibitor in case of highly aggressive AML in U-937, K-562, and Nb4 cell lines while its encouraging role for FKH-1 growth calls for intricate studies to better understand tumorigenesis in t (6,9) AML.