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Research Articles: Therapeutics

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

¹ Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York and ² Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Yuesheng Zhang, Department of Chemoprevention, Roswell Park Cancer Institute, Elm and Carlton Streets, Science 711, Buffalo, NY 14263. Phone 716-845-3097; Fax: 716-845-1144. E-mail: yuesheng.zhang{at}roswellpark.org

Abstract

We have previously shown that broccoli sprouts are a rich source of chemopreventive isothiocyanates, which potently induce carcinogen-detoxifying enzymes and inhibit the development of mammary and skin tumors in rodents. However, the principal isothiocyanate present in broccoli sprout extracts, sulforaphane, not only induces carcinogen-detoxifying enzymes but also activates apoptosis and blocks cell cycle progression. In this article, we show that an aqueous extract of broccoli sprouts potently inhibits the growth of human bladder carcinoma cells in culture and that this inhibition is almost exclusively due to the isothiocyanates. Isothiocyanates are present in broccoli sprouts as their glucosinolate precursors and blocking their conversion to isothiocyanates abolishes the antiproliferative activity of the extract. Moreover, the potency of isothiocyanates in the extract in inhibiting cancer cell growth was almost identical to that of synthetic sulforaphane, as judged by their IC₅₀ values (6.6 versus 6.8 µmol/L), suggesting that other isothiocyanates in the extract may be biologically similar to sulforaphane and that nonisothiocyanate substances in the extract may not interfere with the antiproliferative activity of the isothiocyanates. Further study showed that the isothiocyanate extract of broccoli sprouts activated the mitochondria-mediated apoptosis pathway and halted cells in S and M phases. Cell cycle arrest was associated with down-regulation of Cdc25C and disruption of mitotic spindles. These data show that broccoli sprout isothiocyanate extract is a highly promising substance for cancer prevention/treatment and that its antiproliferative activity is exclusively derived from isothiocyanates. [Mol Cancer Ther 2006;5(4):935–44]

Grant support: USPHS grants CA100623 and CA93780, and The Lewis B. and Dorothy Cullman Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Jed W. Fahey and The Johns Hopkins University own stock in Brassica Protection Products LLC, which sells broccoli sprouts. He is a founder of and an unpaid scientific consultant to Brassica Protection Products, and his stock is subject to certain restrictions under University policy. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Received 11/17/05; revised 12/22/05; accepted 2/21/06.

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