Apoptotic Induction by 1,5-Diaryl-1,4-pentadien-3-one Derivatives in the HL60 Cell Line: In Vitro and In Silico...

Despite advancements in therapeutic agents, cancer treatment, especially for leukemia, is still a formidable challenge for the clinician. The promyelocytic leukemia cell line, HL-60, is widely used for the assessment of the antileukemic potential of new compounds. The current study is designed to investigate the anti-cancer potential of 1,5-diaryl-1,4-pentadien-3-one (DPO) derivatives [Elliptinium Acetate 1, Naphthol AS-BI 2, Alpha-Cyclopiazonic acid 3, Naphthalen-1-yl(1-pentyl-1H-pyrrol-3-yl) methanone 4, and Oxaprozin 5] using cell viability assay and induction of apoptosis.

The anticancer activity was checked against the HL-60 cell line using an MTT assay, followed by apoptotic assay, molecular docking, and molecular dynamics (MD) simulation studies. The Desmond simulation package of Schrodinger (v.2022-1) was employed to perform MD simulations analysis.

The DPO derivatives reduce the cell viability of HL-60 cell lines. Similarly, the active compounds are tested against a human fibroblast cell line (BJ cells). Compound 2 was noncytotoxic, while compounds 1 and 5 were cytotoxic to the BJ cell line. The apoptotic assay was performed for compound 2, which showed 0.5% necrotic cells, 67.2% early, and 22.6% late apoptosis in HL-60 cells after 24 h of incubation. Molecular docking demonstrated that the tested compound (compound 2) interacted with topoisomerase IIb via hydrophobic interactions. Moreover, the topoisomerase II interacted with several residues within the hydrophobic pocket, including Ile125, Pro126, Val137, and Ile217. The RMSD plots for compounds 1-5 and doxorubicin in complex with topoisomerase IIb indicated stabilization of the topoisomerase IIb complex over time.

Naphthol AS-BI 2 exhibits significant antileukemic activity and warrants further investigation to explore its clinical potential in leukemia therapy.