Isothiocyanates as novel cytotoxic and cytostatic agents: molecular pathway on human transformed and non-transformed cells Carmela Fimognari a,* , Michael Nu ¨sse b , Fausto Berti a , Renato Iori c , Giorgio Cantelli-Forti a , Patrizia Hrelia a a Department of Pharmacology, University of Bologna, I-40126 Bologna, Italy b GSF-Flow Cytometry Group, D-85758 Neuherberg, Germany c Istituto Sperimentale per le Colture Industriali, MiPAF, Bologna, Italy Received 4 February 2004; accepted 25 March 2004 Abstract Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Recently, isothiocyanates, natural products found in the diet of humans, has been shown to function as cancer chemopreventive agents. They are strong inhibitors of phase I enzymes and inducers of phase II enzymes. They can also induce apoptosis and modulate cell-cycle progression of highly proliferating cancer cells. This commentary will review the mechanism of apoptosis and growth inhibition mediated by different isothiocyanates. Particular attention will be given to the effects of the new isothiocyanate 4-(methylthio)butylisothiocyanate (MTBITC). Since selective targeting and low toxicity for normal host tissues are fundamental requisites for proposed chemopreventive agents, we will also review the effects of different isothiocyanates on non- transformed human cells. # 2004 Elsevier Inc. All rights reserved. Keywords: Isothiocyanates; Apoptosis; Cell cycle; Cancer cells; Non-transformed cells; Selectivity 1. Introduction According to the multistep carcinogenesis concept, cancer develops in a series of steps, with accumulation of molecular changes progressing through preinvasive histological changes to invasive disease [1]. The earliest events of this process are mutations, deletions, or polysomy at the genomic level, which are successively translated into cellular morphological changes or tissue structural changes [2]. Uncontrolled proliferation, invasion, and metastasis are additional events necessary to induce phenotypic, then physiological, modifications in the tissue. Cancer chemoprevention encompasses the concepts of inhibition, reversal, and retardation of the cancer process through the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer [3]. Epidemiological studies indicate that vegetables and fruit can prevent a variety of human cancers [4] through the action of antioxidants such as carotenoids, vitamin E, etc., suggesting that such agents may be able to protect cells from the mutagenic action of reactive oxygen species [5]. The pioneering works of Wattenberg [6], Talalay et al. [7], and Conney et al. [8] have shown that dietary chemi- cals can prevent chemical carcinogenesis in the laboratory and experimental animals. A group of vegetables with considerable anticarcino- genic properties are the cruciferous vegetables. Cruciferae comprise a large number of vegetables (such as red cab- bage, white cabbage, cauliflower, Brussels sprouts and broccoli) that are among the most frequently consumed Biochemical Pharmacology 68 (2004) 1133–1138 0006-2952/$ – see front matter # 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2004.03.044 Abbreviations: CDK, cyclin-dependent kinase; GSH, glutathione; GST, glutathione-S-transferase; MTBITC, 4-(methylthio)butylisothiocyanate; PI, propidium iodide * Corresponding author. Tel.: þ39 051 209 56 36; fax: þ39 051 209 56 24. E-mail address: carmela.fimognari@unibo.it (C. Fimognari).