Carcinogenesis Advance Access published online on October 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm208
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3-morpholinoproply isothiocyanate (3MP-ITC) is a novel synthetic isothiocyanate that strongly induces the antioxidant response element (ARE)-dependent Nrf2-mediated detoxifying/antioxidant enzymes in vitro and in vivo
1 Department of Pharmaceutics
2 Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854
3 To whom correspondence should be addressed: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854. Tel: 732-445-3831 ext 228. Fax: 732-445-3134. E-mail: KongT{at}rci.rutgers.edu
The induction of Nrf2-mediated detoxifying/antioxidant enzymes is recognized as an effective strategy for cancer chemoprevention. Here, we report that 3-morpholinopropyl isothiocyanate (3MP-ITC) is an exceptionally strong chemical inducer of these enzymes. Exposure of 3MP-ITC in HepG2C8 cells not only induced endogenous Nrf2 protein, but also suppressed endogenous Keap1 protein, resulting in an increased nuclear accumulation of Nrf2. Using chemical inhibitors of protein synthesis (cycloheximide) and 26S proteosomal degradation (MG-132), we observed that the induction of Nrf2 protein by 3MP-ITC appeared to be post-translationally regulated. 3MP-ITC activated ERK1/2 and JNK1/2 and the activation of ARE by 3MP-ITC was significantly attenuated by chemical inhibition of PKC and PI3K signaling pathways in HepG2C8 cells. Treatment with 3MP-ITC significantly depleted the intracellular level of GSH in HepG2C8 cells and oral administration of 3MP-ITC increased the protein expression of hepatic NQO1 and Nrf2 in Nrf2 (+/+), but not in Nrf2 (-/-) mice, whereas UGT1A1 was induced in both genotypes. Our results indicate that 3MP-ITC is a novel isothiocyanate that strongly induces Nrf2-dependent ARE-mediated detoxifying/antioxidant enzymes in vitro and in vivo via the Nrf2 signaling pathway coupled with GSH depletion and activation of multiple signaling kinase pathways, which could be potentially useful agent for cancer chemoprevention.
Key Words: Isothiocyanates (ITCs) • 3-morpholinopropyl Isothiocyanate (3MP-ITC) • Antioxidant Response Element (ARE) • NF-E2-related Factor-2 (Nrf2) • Mitogen-Activated Protein Kinases (MAPKs) • Glutathione (GSH) • N-acetylcycteine (NAC) • Buthionine Sulfoximine (BSO)
Received December 12, 2006; revised August 20, 2007; accepted September 12, 2007.