Effects of naphthyl derivatives on cell physiology of human leukaemia cells: Survival, cell cycle arrest and apoptosis

By 2030, the incidence of new cases of cancer worldwide is expected to have increased by 18.1%, with a 22% increase in mortality. Leukaemia is the most common childhood cancer, and drug resistance remains a major therapeutic challenge. Many factors contribute to drug resistance, including inhibition of apoptotic cell death. Natural product-based drugs have led to significant advances in the treatment of human cancer. Due to their polyphenol structure, flavonoids exhibit various pharmacological properties, including antitumor activities. Here we evaluated the effects of twenty compounds including naphthyl chalcones and intermediates of flavones on viability of human leukaemia cells. Seven compounds showed growth inhibition against HL-60, U-937, MOLT-3, JURKAT, NALM-6 and the overexpressing Bcl-2 protein U-937/Bcl-2. Almost all IC 50 values were below 10 µM, and, for HL-60 and U937, the naphthyl ester 6c and the naphthyl diketone 8a compounds showed IC 50 values that were very similar to the standard therapeutic drug etoposide. Treatment of HL-60 and U-937 with 6c and 8a caused an increase in the percentage of sub-G 1 cells, G 2 -M cell cycle phase arrest, activation and processing of caspases, poly(ADP-ribose) polymerase cleavage and cytochrome c release from mitochondria. Moreover, cell death was partially blocked by the general inhibitor of caspases z-VAD-fmk. Interestingly, the overexpression of Bcl-2 did not prevent U-937/Bcl-2 cells from dying. • SAR of 20 naphthyl derivatives on human leukaemia cells were evaluated. • Naphthyl derivatives included chalcones, esters, β-diketones and flavones. • Seven compounds showed viability inhibition against six leukaemia cell lines. • Naphthyl ester 6c and naphthyl diketone 8a induce G 2 -M phase arrest and apoptosis. • Cell death induced by 6c and 8a was associated with caspase activation.