Abstract
Although the effects of sanguinarine, a benzophenanthridine alkaloid, on the inhibition of some kinds of cancer cell growth have been established, the underlying mechanisms are not completely understood. This study investigated possible mechanisms by which sanguinarine exerts its anticancer action in cultured human bladder cancer cell lines (T24, EJ, and 5637). Sanguinarine treatment resulted in concentration-response growth inhibition of the bladder cancer cells by inducing apoptosis. Sanguinarine-induced apoptosis was correlated with the up-regulation of Bax, the down-regulation of Bid and XIAP, the activation of caspases (-3, -8, and -9), and the generation of increased reactive oxygen species (ROS). The ROS scavenger N-acetyl cysteine (NAC) completely reversed the sanguinarine-triggered apoptotic events. In addition, sanguinarine effectively increased the activation of the c-Jun N-terminal kinase (JNK) and the expression of the early growth response gene-1 (Egr-1), which was recovered by pretreatment with NAC. Furthermore, knockdown of Egr-1 expression by small interfering RNA attenuated sanguinarine-induced apoptosis, but not the JNK inhibitor, indicating that the interception of ROS generation blocked the sanguinarine-induced apoptotic effects via deregulation of the expression of Egr-1 proteins. Taken together, the data provide evidence that sanguinarine is a potent anticancer agent, which inhibits the growth of bladder cancer cells and induces their apoptosis through the generation of free radicals.
Highlights
Benzo[c]phenanthridine alkaloids (BAs) are a relatively small group of isochinoline alkaloids, which have been detected in many plant species of the families Papaveraceae, Fumariaceae, Ranunculaceae, and Rutaceae [1]
To study the mechanisms by which sanguinarine treatment induces apoptosis in bladder cancer cells, the present study examined a number of markers associated with apoptotic cell death
Caspase-8 mediates the intrinsic pathway via cleavage of the proapoptotic Bid protein, a BH3-only protein, to a truncated Bid through translocation from the cytosol to the mitochondria, triggering mitochondrial dysfunction, followed by activation of caspase-9 [41]
Summary
Benzo[c]phenanthridine alkaloids (BAs) are a relatively small group of isochinoline alkaloids, which have been detected in many plant species of the families Papaveraceae, Fumariaceae, Ranunculaceae, and Rutaceae [1]. Recent data have demonstrated that this compound can induce apoptosis in a variety of cancer cell lines in vitro; it does not show any toxic effects on normal cells when administered at similar doses [7,8,9,10,11,12,13,14,15,16]. Reactive oxygen species (ROS) are highly reactive molecules. They include superoxide anion radicals, hydrogen peroxide, singlet oxygen, and hydroxyl radicals. Recent studies suggest that the generation of ROS by sanguinarine initiates cascades of cell death signals in some human cancer cell lines in vitro [12,13,15]
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