Augmentation of the Benzyl Isothiocyanate-Induced Antiproliferation by NBDHEX in the HCT-116 Human Colorectal Cancer Cell Line
- Int J Mol Sci. 2025 Aug 22;26(17):8145. doi: 10.3390/ijms26178145.
- 1. Graduate School of Environmental and Life Science, Okayama University, Okayama 700-8530, Japan.
- 2. School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China.
- 3. Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan.
- 4. Graduate School of Environmental, Life, Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.
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.