Melatonin Increases the Chemosensitivity of Diffuse Large B Cell Lymphoma Cells to Epirubicin By Inhibiting P-Glycoprotein Expression Via the NF-Κb Pathway

Epirubicin (EPI) is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, such as P-glycoprotein (P-gp), renders EPI ineffective. On the basis of some studies, melatonin (MLT) is considered to possess the potential for chemotherapeutic synergy that can be leveraged to overcome MDR. In this study, we investigated the effect of MLT on the sensitivity of DLBCL cells to EPI. The human DLBCL cells SUDHL-6 and SUDHL-10 were incubated with MLT and/or EPI for 48 h. We found that MLT significantly enhanced the EPI-induced suppression of cell proliferation and EPI-induced apoptosis and reduced the IC50 value of the EPI-treated cells. We also found that MLT synergized with EPI to promote the activation of the mitochondria-mediated apoptosis pathway. Further mechanistic studies demonstrated that the sensitivity of DLBCL cells to EPI may be affected by the MLT influence on the expression and function of P-gp. Immunohistochemical staining studies in DLBCL cells from tumor tissues revealed that the expression of P-gp was positively correlated with NF-κB P65 expression. EPI was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Further, we found that MLT reduced the amount of NF-κB P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. In conclusion, our results demonstrated that MLT inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the EPI that suppresses their growth.