Abstract:
Indomethacin (INDO) and diclofenac (DIC) are non-steroidal anti-inflammatory (NSAIDs) have been reported their anticancer potential. Their cytotoxicity could be increased when combining with certain natural compounds such as piperine in Piper plants. N-trans-p-coumaroyltyramine (TCT) (a coumaric acid derivative) was also found at significant amount in these plants and other commonly used in traditional medicine. This study determined the potentiative effect of TCT on NSAIDs (INDO and DIC) induced cytotoxicity in MCF-7 breast cancer cells, and the underlying mechanisms. Combination of TCT with either NSAIDs or various ER stressors at their non-cytotoxic concentrations were able to reduce cell viability in MCF-7 and mitoxantrone-resistant MCF-7/MX cells after 48 h treatment. In this study, MCF-7/MX cells expressed higher activities of efflux transporter (BCRP) than the parental MCF-7 cells. The results showed that TCT had no inhibitory effect on their activities, suggesting that the potentiation was independent of transporters. Evidently, combination of TCT with either NSAIDs or ER stressors significantly reduced mitochondria membrane potential (MMP) in concurrent with the rising of Bax/BcL-2 ratio and apoptosis in both MCF-7 cell types. Furthermore, the combination also resulted in decreased expression of survival proteins p-Nrf-2/HO-1, and increased activation of the endoplasmic reticulum (ER) stress signaling PERK/eIF-2a/ATF-4/CHOP pathways. In conclusion, TCT could increase INDO or DIC cytotoxicity of MCF-7 cells by promoting ER stress-dependent apoptosis in MCF-7 breast cancer cells.
