Sun Ruitong, Yano Aina, Satoh Ayano, Munemasa Shintaro, Murata Yoshiyuki, Nakamura Toshiyuki, Nakamura Yoshimasa
Graduate School of Environmental and Life Science, Okayama University, Okayama 700-8530, Japan.
School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China.
Int J Mol Sci. 2025 Aug 22;26(17):8145. doi: 10.3390/ijms26178145.
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 -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.
药物代谢和消除的增加是介导对化疗药物以及抗癌天然产物（如异硫氰酸苄酯（BITC））多药耐药（MDR）的重要机制。为了评估联合使用某种化合物克服这种耐药性的可能性，我们聚焦于BITC的谷胱甘肽 - 转移酶（GST）依赖性代谢。对π类GST选择性抑制剂6 -（7 - 硝基 - 2,1,3 - 苯并恶二唑 - 4 - 基硫代）己醇（NBDHEX）进行药理处理，显著增加了BITC对人结肠癌细胞HCT - 116的毒性。然而，NBDHEX意外地增加了BITC - 谷胱甘肽（GSH）共轭物以及BITC修饰蛋白的水平，这表明NBDHEX可能通过抑制BITC - GSH排泄而非抑制GST来增加BITC修饰蛋白的积累。此外，NBDHEX通过增强凋亡相关途径（如c - Jun N末端激酶和半胱天冬酶 - 3途径）的激活，显著增强了BITC诱导的凋亡。这些结果表明，NBDHEX联合治疗可能是一种克服药物外排介导的多药耐药并因此在较低剂量下诱导BITC生物活性的有效方法。
