Effects of Thymoquinone–Fatty Acid Conjugates on Cancer Cells

More than the sum of its parts : The seeds of Nigella sativa have been a traditional herbal remedy for ailments such as asthma, diarrhea, and cancer. Their essential oil is rich in polyunsaturated fatty acids and thymoquinone. By linking them covalently, a tremendous boost in anticancer activity can be achieved in resistant tumor cells.4‐Acylhydrazones and 6‐alkyl derivatives of thymoquinone (TQ) were tested for growth inhibition of human HL‐60 leukemia, 518A2 melanoma, KB‐V1/Vbl cervix, and MCF‐7/Topo breast carcinoma cells. Unsaturated side chains conferred greater activities than equally long saturated chains. The number of CC bonds was less decisive than chain length. The 6‐hencosahexaenyl conjugate 3 e was most active in all resistant tumor cells, with IC 50 (72 h) values as low as 30 n M in MCF‐7/Topo cells. The conjugates are likely to operate by mechanisms different from that of TQ. For instance, 3 e induced distinct caspase‐independent apoptosis in HL‐60 and 518A2 cells concomitant with a loss of mitochondrial membrane potential and a subsequent rise in the levels of reactive oxygen species.