Dietary Isothiocyanates Inhibit the Growth of Human Bladder Carcinoma Cells

Abstract

Many isothiocyanates (ITCs), some of which are abundant in cruciferous vegetables, have been repeatedly shown to inhibit carcinogenesis in a variety of rodent organs. However, several naturally occurring ITCs also promoted bladder tumorigenesis in rodents, raising the question of whether ITCs behave differently in bladder cells. Alternatively, the observed carcinogenic effects of ITCs may result from prolonged exposure of the bladder epithelium, where the tumors originate, to high concentrations of electrophilic ITCs in the urine. Ingested ITCs are almost exclusively excreted and highly concentrated in the urine as N-acetylcysteine conjugates (NAC-ITC). While several NAC-ITCs also are known anticarcinogens, they are unstable and readily dissociate into parent ITCs. In this study, ITCs, including those that have carcinogenic potential in the rodent bladders, induced apoptosis and/or arrested cell-cycle progression in 2 human bladder carcinoma lines (UM-UC-3 and T24) at 7.5-30 micromol/L. Multiple caspases, including caspase-9, -8, and -3, as well as poly(ADP-ribose)polymerase, were cleaved upon ITC exposure. The ITCs blocked cell-cycle progression at the G(2)/M and/or S phases in these cells and downregulated several cell-cycle regulators. However, further increases in ITC concentrations abolished their activities, described above. These findings show that urinary ITC concentrations may need to be maintained at low micromolar concentrations for bladder cancer prevention.

Potent activation of mitochondria-mediated apoptosis and arrest in S and M phases of cancer cells by a broccoli sprout extract

“…We previously showed that several isothiocyanates, including sulforaphane, induced apoptosis and cell cycle arrest in this cell line (17). Our current results show that the broccoli sprout extracts impart potent antiproliferative activity and that such activity depends almost entirely on the enzymatic conversion of glucosinolates to isothiocyanates.…”

“…Sulforaphane was previously shown to induce apoptosis of UM-UC-3 cells at 7.5 to 30 Amol/L, which was associated with mitochondrial damage, cytoplasmic relocation of cytochrome c, cleavage/activation of caspase-9 and caspase-3, as well as cleavage of poly(ADP-ribose)-polymerase (17,23). The isothiocyanates in broccoli sprout extracts behaved similarly.…”

Suppressive effect of 1,4-phenylene diisothiocyanate onN-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice

“…15,53 Dietary exposure of DITC in the post-initiation phase decreased BrdU-LI and cyclin D1 positive cell ratios in urinary bladder tumors, but did not significantly reduce the development of urinary bladder tumors. Recently, Tang and Zhang 54 found that ITC blocked cell-cycle progression and downregulated several cellcycle regulators in human bladder carcinoma cells in certain concentration. The cytostatic activity of DITC in promotion phase was lower than that in initiation phase.…”

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

“…Bladder cancer is particularly interesting because dietary isothiocyanates, a group of key anticarcinogens occurring in cruciferous vegetables, show potent chemopreventive effects against bladder cancer in both in vitro and in vivo models (4)(5)(6)(7)(8)(9). Moreover, the unique in vivo pharmacokinetics and disposition of orally ingested isothiocyanates in humans renders the bladder the best targeted organ for the anticancer effect of dietary isothiocyanates (5).…”