4-methylthiobutyl isothiocyanate synergize the antiproliferative and pro-apoptotic effects of paclitaxel in human breast cancer cells

Multidrug resistance (MDR) is considered as a major obstacle in achieving an effective treatment of breast cancer. Paclitaxel has been used to treat cancers of the cervical, breast, ovarian and brain but MDR limits its therapeutic potential. Phytochemicals have received much interest in recent decades especially in combination approaches to tackle MDR due to their negligible harm to healthy cells and synergistic potential. Considering this notion, the present study aimed at investigating the synergistic activity of 4-MTBITC and PTX against a panel of breast cancer cells. Our results revealed that the combination had a significant antiproliferative activity against T-47D cells. Mechanistic studies revealed that 4-MTBITC and PTX also promoted the production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential. In the presence of 4-MTBITC- PTX, T-47D cells were found to be arrested in the G(2)/M phase which also confirmed the enhancement of late apoptotic cell population in the flow cytometer analysis. In western blot experiment, the combination had a significant decrease in Bcl-xl protein level, whereas a higher level of p53, cleaved caspase-3, and cleaved caspase-9 proteins compared to individual treatment in T-47D cells. The RT-qPCR analysis also showed that the combination had significant upregulation in the gene expression of p53, cytochrome-c, Apaf-1 and downregulation in the expression of Bcl-2 gene in T-47D cells. Hence, all the results showed that a combination of 4-MTBITC-PTX significantly enhanced the apoptosis pathway in the T-47D cell line which indicates its clinical application for the treatment of breast cancer.

Automated summary

Multidrug resistance (MDR) is a major barrier in treating breast cancer, but a combination of 4-MTBITC-PTX can significantly enhance the apoptosis pathway in T-47D cells, indicating its clinical application for breast cancer treatment. The combination has a synergistic antiproliferative activity and promotes the production of reactive oxygen species (ROS) while reducing mitochondrial membrane potential. Mechanistic studies also show that the combination arrests T-47D cells in the G(2)/M phase and increases late apoptotic cell population. Moreover, it decreases the protein level of Bcl-xl and increases the levels of p53, cleaved caspase-3, and cleaved caspase-9.