Apoptotic Effects of a Thioether Analog of Vitamin K₃ in a Human Leukemia Cell Line

Research suggests that thioether analogs of vitamin K₃ (VK₃) can act to preserve the phosphorylation of epidermal growth factor receptors by blocking enzymes (phosphatases) responsible for their dephosphorylation. Additionally, these derivatives can induce apoptosis via mitogen-activated protein kinase and caspase-3 activation, inducing reactive oxygen species (ROS) production, and apoptosis. However, vitamin K₁ exhibits only weak inhibition of phosphatase activity, while the ability of VK₃ to cause oxidative DNA damage has raised concerns about carcinogenicity. Hence, in the current study, we designed, synthesized, and screened a number of VK₃ analogs for their ability to enhance phosphorylation activity, without inducing off-target effects, such as DNA damage. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay revealed that each analog produced a different level of cytotoxicity in the Jurkat human leukemia cell line; however, none elicited a cytotoxic effect that differed significantly from that of the control. Of the VK₃ analogs, CPD5 exhibited the lowest EC₅₀, and flow cytometry results showed that apoptosis was induced at final concentrations of ≥10 μM; hence, only 0.1, 1, and 10 μM were evaluated in subsequent assays. Furthermore, CPD5 did not cause vitamin K-attributed ROS generation and was found to be associated with a significant increase in caspase 3 expression, indicating that, of the synthesized thioether VK₃ analogs, CPD5 was a more potent inducer of apoptosis than VK₃. Hence, further elucidation of the apoptosis-inducing effect of CPD5 may reveal its efficacy in other neoplastic cells and its potential as a medication.