Evaluation of anti-proliferative activity of Bismuth Phenanthroline against human myeloid leukemia

Abstract

Leukemia is the cancer of blood-forming tissues that causes the overproduction of immature blood cells. Tyrosine kinase inhibitors and all trans retinoic acid (ATRA) + arsenic trioxide; are the standard of care therapies available for chronic myeloid leukemia (CML) and acute promyelocytic leukemia (APL), respectively. Even though these current therapies can achieve complete remission by reducing the tumor burden, de novo and adaptive resistance to imatinib, differentiation syndrome by ATRA and ATO toxicity are limiting the treatment response rate amongst leukemia patients. Organometallic compounds are attractive anticancer drug candidates that have been proved successful in treating solid cancers. In the current study, the reactivity of a novel organometallic compound Bismuth Phenanthroline (Bi Phen) has been analyzed, both in silico and in vitro, in terms of its capacity to inhibit leukemia cell growth. Molecular docking studies through AutoDock4.2 revealed Bi Phen binding energy of −6.23 kJ mol−1 towards BCR in Ph+ CML and −7.0 kJ mol−1 towards the receptor protein RARα in APL, implying that Bi Phen has a good binding affinity for its target proteins. The antiproliferative effects of Bi Phen on the BCR/ABL-bearing CML cells and PML/RARα-bearing APL cells were analyzed through MTT assay. The results indicated that Bi Phen was able to inhibit growth in these cells at μM concentrations (0.625, 1.25, 2.5), in a dose-dependent manner. Further, mechanistic studies through real-time PCR revealed that Bi Phen might have interfered with the β-catenin dependent leukemogenesis in CML and APL. Future studies of this compound on primary materials and in vivo tumor models may provide a strong rationale for the potential application of Bi Phen as a novel agent against leukemia.