ABSTRACT
Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3(4,5dimethyl2thiazol)2,5diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT8/5Fu cells and provided evidence that activated nuclear factor erythroid 2related factor (Nrf2) deficiency induced by the curcumin altered the Bcell lymphoma 2 (Bcl2) associated X protein/Bcl2 expression ratio, which led to the induction of apoptosis in HCT8/5Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.
Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , NF-E2-Related Factor 2/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Fluorouracil/pharmacology , Genes, bcl-2 , Humans , Signal Transduction/drug effects , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolismABSTRACT
OBJECTIVE: To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway. METHODS: A drug-resistant cell model was established by exposing A549/CDDP cell to 2 µg/mL CDDP. A549/CDDP cell was treated with 20 µg/mL CDDP and 10 µM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed. RESULTS: CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin. CONCLUSIONS: The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell. Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.
