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
