Isothiocyanates in the chemoprevention of bladder cancer
ITCs are a class of well-known cancer-preventive phytochemicals. The unique in vivo pharmacokinetics of orally ingested ITCs makes the bladder, especially the bladder epithelium that gives rise to the majority of bladder cancer, perhaps the most exposed tissue to ITCs and their bioactive metabolites in vivo . As a result, select ITCs may be especially useful for the prevention of both primary and recurrent bladder cancer. The presented research is focused on the cancer chemopreventive activities and the underlying mechanisms of four common dietary ITCs and their principle urinary metabolites (N-acetylcysteine conjugates, NAC-ITCs) in human bladder cancer cells. We demonstrate that both ITCs and NAC-ITCs exert potent antiproliferative activities against human bladder cancer cells, regardless of the degree of malignancy and drug-resistant status of cells. They elicit very similar antiproliferative responses, including induction of apoptosis via activating the mitochondria-mediated apoptotic pathway, and arrest of cell cycle progression via disrupting the mitotic spindle and down-regulating Cdc25C. Our results also show that NAC-ITCs are pro-drugs of ITCs: NAC-ITCs must dissociate to ITCs in order to enter the cells and exert their biological activities. These findings have important clinical implications. Both ITCs and NAC-ITCs inhibit the proliferation of bladder cancer cells at low μM concentrations (7.5-15 μM), which appear to be readily achievable in vivo . Moreover, ITCs may be delivered to humans using vegetable extracts. We show that broccoli sprout extract, which is rich in SF, potently inhibits the growth of human bladder cancer cells and that the potency of broccoli sprout extract in inhibiting cancer cell growth, as well as its antiproliferative mechanisms, are almost identical to those of SF. Thus, our studies show that ITC-rich broccoli sprout extract is a highly promising substance for potential bladder cancer chemoprevention.