Augmentation of the Benzyl Isothiocyanate-Induced Antiproliferation by NBDHEX in the HCT-116 Human Colorectal Cancer
Ruitong Sun1,2, Aina Yano1, Ayano Satoh3
1Graduate School of Environmental and Life Science, Okayama University, Okayama 700-8530, Japan.
Abstract:
Increased drug metabolism and elimination are prominent mechanisms mediating multidrug resistance (MDR) to not only chemotherapy drugs but also anti-cancer natural products, such as benzyl isothiocyanate (BITC). To evaluate the possibility of combined utilization of a certain compound to overcome this resistance, we focused on glutathione S-transferase (GST)-dependent metabolism of BITC. The pharmacological treatment of a pi-class GST-selective inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), significantly increased BITC-induced toxicity in human colorectal cancer HCT-116 cells. However, NBDHEX unexpectedly increased the level of the BITC-glutathione (GSH) conjugate as well as BITC-modified proteins, suggesting that NBDHEX might increase BITC-modified protein accumulation by inhibiting BITC-GSH excretion instead of inhibiting GST. Furthermore, NBDHEX significantly potentiated BITC-induced apoptosis with the enhanced activation of apoptosis-related pathways, such as c-Jun N-terminal kinase and caspase-3 pathways. These results suggested that combination treatment with NBDHEX may be an effective way to overcome MDR with drug efflux and thus induce the biological activity of BITC at lower doses.
Insights
Combining benzyl isothiocyanate (BITC) with NBDHEX, a drug efflux inhibitor, enhances anti-cancer effects in colorectal cancer cells. This combination overcomes multidrug resistance (MDR) by increasing BITC-induced apoptosis.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Multidrug resistance (MDR) limits chemotherapy efficacy.
- Benzyl isothiocyanate (BITC) is a natural product with anti-cancer potential.
- Glutathione S-transferase (GST) enzymes mediate drug metabolism and resistance.
Purpose of the Study:
- To investigate if inhibiting GST-dependent BITC metabolism can overcome MDR.
- To evaluate the combined effect of BITC and a GST-selective inhibitor (NBDHEX) on colorectal cancer cells.
Main Methods:
- Treatment of HCT-116 colorectal cancer cells with BITC and NBDHEX.
- Measurement of BITC-glutathione (GSH) conjugate levels and BITC-modified proteins.
- Assessment of apoptosis-related pathways, including c-Jun N-terminal kinase and caspase-3 activation.
Main Results:
- NBDHEX significantly increased BITC-induced toxicity in HCT-116 cells.
- NBDHEX enhanced BITC-GSH conjugate and BITC-modified protein levels, suggesting inhibition of drug efflux.
- Combination treatment potentiated BITC-induced apoptosis via enhanced activation of apoptosis pathways.
Conclusions:
- NBDHEX may overcome MDR by inhibiting BITC-GSH excretion rather than GST activity.
- Combination therapy with NBDHEX could be a strategy to enhance BITC's anti-cancer activity at lower doses.
- Targeting drug efflux mechanisms alongside cytotoxic agents shows promise for overcoming cancer resistance.
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