3-Morpholinopropyl isothiocyanate is a novel synthetic isothiocyanate that strongly induces the antioxidant response element-dependent Nrf2-mediated detoxifying/antioxidant enzymes in vitro and in vivo.
The induction of NF-E2-related factor-2 (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 Kelch-like ECH-associated protein 1, 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 antioxidant response element (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 glutathione (GSH) in HepG2C8 cells and oral administration of 3MP-ITC increased the protein expression of hepatic NAD[P]H:quinone oxidoreductase-1 and Nrf2 in Nrf2 (+/+) but not in Nrf2 (-/-) mice, whereas UDP-glucuronosyl transferase 1A1 was induced in both genotypes. Our results indicate that 3MP-ITC is a novel ITC 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.
Keum
Young-Sam
YS
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Chang
Peter Pil-Jae
PP
Kwon
Ki Han
KH
Yuan
Xiaoling
X
Li
Wenge
W
Hu
Longqin
L
Kong
Ah-Ng Tony
AN
D000975:Antioxidants / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C527796:3-morpholinopropyl isothiocyanate; D000975:Antioxidants; D017931:DNA Primers; D017879:Isothiocyanates; D009025:Morpholines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011494:Protein Kinases; D005978:Glutathione