To Evaluate the Anti-Proliferative Effect ofImidazole Derivatives in Acute Promyelocytic Leukemia

Abstract

The commencement of leukemia is associated with continual proliferation of undifferentiated and immature white blood cells as cells do not undergo terminal differentiation due to maturation arrest. Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML) accounting 10-15% of newly diagnosed AML, and predominantly characterized by a balanced translocation; t (15; 17) leads to PML/RARα fusion gene. The PML/RARα fusion onco-protein induce leukemia by blocking differentiation at promyelocytic stage. Currently, APL is treated with All trans retinoic acid (ATRA), Arsenic trioxide (ATO), chemotherapy, and combinations, ATRA and ATO both targets fusion protein PML/RARα, ATRA induces differentiation while ATO induce apoptosis and promotes differentiation. But resistance development, differentiation syndrome and poisoning by ATO are still major issues need to be overcome. In this regard, imidazole derived compounds are of great interest among scientists for development of potential anticancer drugs as they have multiple biological activities including anticancer, antifungal, , antibacterial, anti-inflammatory, antineuropathic, and many more. The present research was designed to test anti-cancerous potential of four novel imidazole derived compounds L7, L4, R-35, and R-NIM04 both in-silico and in-vitro against PML-RARα positive APL. In-silico results of the study indicated RARα protein as potential drug target in APL. Furthermore, in-vitro results showed that treatment with L7, L4, R-35 & R NIM04 at the different concentrations considerably reduced the proliferation of PML-RARα positive APL (p-values <0.001). The expression analysis through Real-time PCR indicated that these imidazole derivatives interferes with the β-catenin dependent leukemiogenesis and downregulates AXL-RTK in APL cells with the expected downregulation of downstream c Myc, related to the Wnt/β-catenin signaling. The past/present researches provide significant evidences of imidazole derivatives as a targeted anti-cancer therapy in future, but to open up new horizons in the field of targeted therapies more in-vitro and in-vivo research is needed