Thymoquinone hydrazone derivatives cause cell cycle arrest in p53-competent colorectal cancer cells.

Thymoquinone (TQ), the major compound of black seed oil, has been shown to induce pro-apoptotic signaling pathways in various human cancer models. Although TQ is commonly used in traditional medicine, its use in humans is limited due to its chemical properties and poor membrane penetration capacity. We therefore attached saturated and unsaturated fatty acid residues to TQ and evaluated the effect on cell proliferation, apoptosis and underlying signaling pathways in HCT116 and HCT116(p53-/-) colon cancer and HepG2 hepatoma cells in vitro. Treatment with thymoquinone-4-α-linolenoylhydrazone (TQ-H-10) or thymoquinone-4-palmitoylhydrazone (TQ-H-11) induced a cytostatic effect, particularly in p53-competent HCT116 cells, mediated by an up-regulation of p21(cip1/waf1) and a down-regulation of cyclin E, and associated with an S/G(2) arrest of the cell cycle. Cells lacking p53 (HCT116(p53-/-)) or HepG2 liver cancer cells showed only a minor response to TQ-H-10. These findings demonstrate that derivatives of TQ inhibit cell proliferation dependent on p53 status by activating the cell cycle inhibitor p21(cip1/waf1) at lower concentrations than unmodified TQ. Structural modifications can therefore contribute to the further clinical development of TQ.