Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing
cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of
drug-metabolizing
enzymes are
sulforaphane, an aliphatic
isothiocyanate, and
brassinin, an
indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel
cancer chemopreventive agent, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-
butane (trivial name,
sulforamate), an aliphatic analogue of
brassinin with structural similarities to
sulforaphane. This compound was shown to be a monofunctional inducer of
NAD(P)H:
quinone oxidoreductase [
quinone reductase (QR)], a Phase II
enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with
sulforaphane (concentration required to double the specific activity of QR, approximately 0.2 microM), but cytotoxicity was reduced by about 3-fold (IC50 approximately 30 microm). In addition,
sulforaphane, as well as the analogue, increased
glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR
mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human
hepatoma cells were transiently transfected with QR-
chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene.
Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 microM by interaction with the
antioxidant responsive
element (5-14-fold induction) without interacting with the
xenobiotic responsive
element. Moreover, both compounds significantly induced mouse mammary QR and
glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic
enzyme activities was less pronounced. Both
sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in
carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 microm, respectively). On the basis of these results, the
sulforaphane analogue can be regarded as a readily available promising new
cancer chemopreventive agent.