Abstract

Background: A novel series of structurally divergent 1,5-diaryl-3-oxo- 1,4-pentadiene analogues 1-10 displayed marked cytotoxic potencies towards a number of human leukemia/lymphoma cells.

Objective: To identify novel selective cytotoxic compounds that induce apoptosis.

Methods: The Differential Nuclear Staining (DNS) screening protocol was utilized to measure the cytotoxicity of all experimental dienones on several cancerous cells. Additionally, the selective cytotoxicity index was calculated by comparing the dienone’s cytotoxicity between leukemia/lymphoma cells vs. non-cancerous cells. Furthermore, to discern whether a selected dienone induced cell death via apoptosis or necrosis on T-lymphocyte leukemia cells, diverse approaches were utilized to detect individual biochemical facets of apoptosis.

Results: The dienones were tested for their anti-neoplastic efficiency on human leukemia/lymphomaderived cell lines. Special emphasis was applied on dienone 1, on the basis of its sub-micromolar cytotoxicity (CC50=0.43+0.02 μM) and high selective cytotoxicity index (11.1) exerted on T-leukemia cells. In general, dienone 1 showed the most potent cytotoxic properties as compared to other dienones and a related reference cytotoxin curcumin as well as the EF-24 curcumin analogue. Dienone 1 caused cell death by apoptosis in Jurkat cells as evidenced by inducing phosphatidylserine externalization, mitochondrial depolarization and caspase-3/7. These effects were mainly attributed to the induction of apoptotic pathways.

Conclusion: The novel dienone 1 was found to exhibit potent anti-leukemia activity by inducing programmed cell death/apoptosis. Consequently, dionone 1 should be developed further to examine its potential efficacy to combat malignancies in a pre-clinical animal model.

Keywords: Apoptosis, cancer, caspase 3, cytotoxins, curcumin analogue, leukemia, mitochondria.

Graphical Abstract