CANCER CHEMOPREVENTIVE POTENTIAL OF SULFORAMATE, A NOVEL ANALOG OF SULFORAPHANE THAT INDUCES PHASE-2 DRUG-METABOLIZING-ENZYMES

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 o f drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyan ate, and brassinin, an indole-based dithiocarbamate, both found in cru ciferous vegetables, We currently report the synthesis and activity of a novel cancer chemopreventive agent, 4-methylsulfinyI-1-(S-methyldit hiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compo und was shown to be a monofunctional inducer of NAD(P)H:quinone oxidor eductase [quinone reductase (QR)I, a Phase II enzyme, in murine Hepa 1 c1c7 cell culture and two mutants thereof, Induction potential was com parable to that observed with sulforaphane (concentration required to double the specific activity of QR, similar to 0.2 mu M), but cytotoxi city was reduced by about 3-fold (IC50 similar to 30 mu m). In additio n, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells, Induction of QR was regula ted 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 i nduction, HepC2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing va rious portions of the 5'-region of the QR gene, Sulforaphane and the a nalogue significantly induced (P < 0.0001) CAT activity at a concentra tion of 12.5 mu M by interaction with the antioxidant responsive eleme nt (5-14-fold induction) without interacting with the xenobiotic respo nsive element. Moreover, both compounds significantly induced mouse ma mmary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme act ivities was less pronounced. Both sulforaphane and the analogue were i dentified as potent inhibitors of preneoplastic lesion formation in ca rcinogen-treated mouse mammary glands in organ culture (84 and 78% inh ibition at 1 mu m, respectively), On the basis of these results, the s ulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.