Structurally Related Anticancer Activity of Flavonoids: Involvement of Reactive Oxygen Species Generation

Abstract

The cytotoxicity and apoptosis induction effect of 23 flavonoids on human leukemia cells (HL‐60) were investigated. 3,6‐Dihydroxyflavone, luteolin and geraldol showed the most potent cytotoxic effect. By comparing the cytotoxicity of selected molecules that differ in only one structure element, we identified several structural properties important for potent cytotoxic activity, including the presence of 2,3‐double bond, appropriate hydroxyl numbers, 3‐OH and ortho‐OH in ring B. Flavonoids with a 5‐OH exhibited lower cytotoxicity than their counterparts. The intracellular reactive oxygen species (ROS) detection showed that 3,6‐dihydroxyflavone, luteolin and geraldol all caused ROS generation. Addition of antioxidant N‐acetylcysteine prevented the elevation of ROS induced by the three flavonoids and partially suppressed their cytotoxic effects. It implied that pro‐oxidation was involved in the apoptotic response, and ROS generation plays an important role in the antitumor effect of flavonoids. PRACTICAL APPLICATIONS Flavonoids exist extensively in foods and herbal products, and several beneficial biological activities have been demonstrated. Development of compounds with anticancer and other pharmacological effects from natural products has currently become a very important topic. Our study revealed structurally related anticancer activities of 23 flavonoids on HL‐60 cells and indicated that 3,6‐dihydroxyflavone, luteolin and geraldol were active anticancer compounds via pro‐oxidation and apoptosis induction. These findings should be useful for developing potent anticancer compounds from flavonoids for potential clinical application.

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