LFE: Lycii Fructus extract; GSH: glutathione; NQO1: NAD(P)H:quinone oxidoreductase 1; HO-1: heme oxygenase-1; GCLC: glutamate-cysteine ligase, catalytic subunit; xCT: a component of cysteine/glutamate antiporter (cystine/glutamate exchanger); CYP1A1: cytochrome P450 1A1; GSH: glutathione; AhR: aryl hydrocarbon receptor; Nrf2: nuclear factor (erythroid-derived 2)-like 2; CGA: chlorogenic acid; RT-PCR: reverse transcription-polymerase chain reaction; DTT: dithiothreitol; PMSF: phenylmethylsulfonyl fluoride; ARE: antioxidant response element; XRE: xenobiotic responsive element.

The increasing drug efflux through the ATP-binding cassette (ABC) transporters is the most plausible mechanism that mediates resistance to the anticancer phytochemicals, such as benzyl isothiocyanate (BITC), as well as chemotherapy drugs. To identify a potential component to overcome this resistance by combinatory utilization, we focused on multidrug resistance-associated proteins (MRPs) pumping various drug metabolites with glutathione as well as the organic anions. The pharmacological treatment of an MRP inhibitor, MK571, significantly potentiated the BITC-induced antiproliferation, coincided with the enhanced accumulation of BITC and glutathione in human colorectal cancer HCT-116 cells. MK571 also enhanced the apoptosis induction as well as activation of the mitogen-activated protein kinases and caspase-3, whereas it did not affect their basal levels. These results suggested that, since MRPs might play a pivotal role in the BITC efflux, MK571 potentiates the BITC-induced antiproliferation in human colorectal cancer cells through inhibition of the glutathione-dependent BITC efflux.