Abstract
Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples of oral leukoplakia. With gene microarray and immunostaining, we found 4-nitroquinoline 1-oxide (4NQO) in drink activated the Nrf2 pathway and produced oxidative damage in mouse tongue. Meanwhile whole exome sequencing of mouse tongue identified mutations consistent with 4NQO's mutagenic profile. Using cultured human oral keratinocytes and 4NQO-treated mouse tongue, we found that SFN pre-treatment activated the NRF2 pathway and inhibited oxidative damage both in vitro and in vivo. On the contrary, a structural analogue of SFN without the isothiocyanate moiety did not have such effects. In a long-term chemoprevention study using wild-type and Nrf2-/- mice, we showed that topical application of SFN activated the NRF2 pathway, inhibited oxidative damage, and prevented 4NQO-induced oral carcinogenesis in an Nrf2-dependent manner. Our data clearly demonstrate that SFN has chemopreventive effects on oxidative stress-associated oral carcinogenesis, and such effects depend on Nrf2 and the isothiocyanate moiety.
Highlights
A solution of the crude 3 (~2g, 7.5 mmol) in anhydrous DMF (8 mL) was added dropwise to a stirred mixture of NaSMe (764 mg, 11.3 mmol, 1.5 eq) in anhydrous DMF (4 mL) at 0 °C within 12 min to give a thick yellow suspension
The solution was concentrated to dryness, and the oily residue was purified by flash column chromatography to give tert-butyl (4-hydroxybutyl)carbamate (2) as colorless oil that solidified to a white solid on standing (2.2g, 99% yield). 1H NMR (500 MHz, CDCl3): δ1.37 (s, 9H), 1.50 (m, 4H), 3.05 (m, 2H), 3.56 (m, 2H); 13C NMR (125 MHz, CDCl3): δ26.71, 28.59, 29.87, 40.48, 62.23, 79.30, 156.47
The combined filtrate was washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated to give mesylate 3 (~2.98g) as a colorless oil that was used in the step without further purification
Summary
A solution of the crude 3 (~2g, 7.5 mmol) in anhydrous DMF (8 mL) was added dropwise to a stirred mixture of NaSMe (764 mg, 11.3 mmol, 1.5 eq) in anhydrous DMF (4 mL) at 0 °C within 12 min to give a thick yellow suspension. The solution was concentrated to dryness, and the oily residue was purified by flash column chromatography (petroleum ether: EtOAc=1:1) to give tert-butyl (4-hydroxybutyl)carbamate (2) as colorless oil that solidified to a white solid on standing (2.2g, 99% yield). MsCl (1.08 mL, 13.92 mmol, 1.2 eq) was added dropwise over 5 min to an ice-cold stirred solution of 2 (2.2g, 11.6 mmol) and Et3N (2.42 mL, 17.4 mmol, 1.5 eq) in anhydrous CH2Cl2 (20 mL).
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