Reversal of multidrug resistance by curcumin through FA/BRCA pathway in multiple myeloma cell line MOLP-2/R.

摘要

Most patients with multiple myeloma (MM) will relapse eventually due to the acquired multidrug resistance (MDR). The objective of this study was to explore the reversal effect of curcumin on the MDR of human MM cell line, MOLP-2/R, and analyze the role of Fanconi anemia (FA)/BRCA pathway in this process. MOLP-2/R was selected by stepwise exposure of parental MOLP-2 cells to increasing concentrations of melphalan. The MTT assay was used to detect the reversal ratio of curcumin. The FANCD2 monoubiquitination expression was detected by western blotting to explore the role of FA/BRCA pathway. Cell cycle, apoptosis, and intracellular drug concentration were analyzed by flow cytometry. The results indicated that combination of melphalan with curcumin had stronger effects on the proliferation inhibition, inducement of apoptosis, G2/M phase arrest, and enhancement of intracellular drug concentration than melphalan alone in MOLP-2/R cells. These effects were accompanied with inhibition of FA/BRCA pathway by down regulation of FANCD2 protein monoubiquitination in a dose-dependent manner. In conclusion, curcumin reversed multidrug resistance of MOLP-2/R through inhibition of FA/BRCA pathway. The possible mechanisms include (1) reduction of DNA damage repair and stimulation of apoptosis of tumor cells through inhibition of FA/BRCA pathway, which is important for DNA repair, and (2) achievement of high concentration in target cells. Curcumin may be a safe reversal agent of multidrug resistance with low-dose DNA cross-linking agents.