Siying Zhou1, Jian Li2, Hanzi Xu3, Sijie Zhang4, Xiu Chen2, Wei Chen5, Sujin Yang2, Shanliang Zhong6, Jianhua Zhao7, Jinhai Tang8. 1. The First Clinical Medical College, Nanjing University of Traditional Chinese Medicine, Xianlin Road 138, Nanjing 210023, Jiangsu, China; Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210023, Jiangsu, China. 2. Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210023, Jiangsu, China; The Fourth Clinical School of Nanjing Medical University, Baiziting 42, Nanjing 210009, Jiangsu, China. 3. The First Clinical Medical College, Nanjing University of Traditional Chinese Medicine, Xianlin Road 138, Nanjing 210023, Jiangsu, China; Department of Radiotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210023, Jiangsu, China. 4. Department of Breath Internal Medicine, Suzhou Hospital of Traditional Chinese Medicine, Yangsu Road 18, Suzhou 215006, Jiangsu, China. 5. Department of Head and Neck Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210023, Jiangsu, China. 6. Center of Clinical Laboratory Science, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210009, Jiangsu, China. 7. Center of Clinical Laboratory Science, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210009, Jiangsu, China. Electronic address: lcjyjhzhao@126.com. 8. The First Clinical Medical College, Nanjing University of Traditional Chinese Medicine, Xianlin Road 138, Nanjing 210023, Jiangsu, China; Department of General Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Baiziting 42, Nanjing 210023, Jiangsu, China; Jiangsu Province Hospital, Guangzhou Road 300, Nanjing 210023, Jiangsu, China. Electronic address: Jhtang305@126.com.
Abstract
BACKGROUND: Emerging evidence suggests that curcumin can overcome drug resistance to classical chemotherapies, but poor bioavailability and low absorption have limited its clinical use and the mechanisms remain unclear. Also, Adriamycin (Adr) is one of the most active cytotoxic agents in breast cancer; however, the high resistant rate of Adr leads to a poor prognosis. METHODS: We utilized encapsulation in liposomes as a strategy to improve the bioavailability of curcumin and demonstrated that liposomal curcumin altered chemosensitivity of Adr-resistant MCF-7 human breast cancer (MCF-7/Adr) by MTT assay. The miRNA and mRNA expression profiles of MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr cells were analyzed by microarray and further confirmed by real-time PCR. We focused on differentially expressed miR-29b-1-5p to explore the involvement of miR-29b-1-5p in the resistance of Adr. Candidate genes of dysregulated miRNAs were identified by prediction algorithms based on gene expression profiles. Networks of KEGG pathways were organized by the selected dysregulated miRNAs. Moreover, protein-protein interaction (PPI) was utilized to map protein interaction networks of curcumin regulated proteins. RESULTS: We first demonstrated liposomal curcumin could rescue part of Adriamycin resistance in breast cancer and further identified 67 differentially expressed microRNAs among MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr. The results showed that lower expressed miR-29b-1-5p decreased the IC50 of MCF-7/Adr cells and higher expressed miR-29b-1-5p, weaken the effects of liposomal curcumin to Adr-resistance. Besides, we found that 20 target genes (mRNAs) of each dysregulated miRNA were not only predicted by prediction algorithms, but also differentially expressed in the microarray. The results showed that MAPK, mTOR, PI3K-Akt, AMPK, TNF, Ras signaling pathways and several target genes such as PPARG, RRM2, SRSF1and EPAS1, may associate with drug resistance of breast cancer cells to Adr. CONCLUSIONS: We determined that an altered miRNA expression pattern is involved in acquiring resistance to Adr, and that liposomal curcumin could change the resistance to Adr through miRNA signaling pathways in breast cancer MCF-7 cells.
BACKGROUND: Emerging evidence suggests that curcumin can overcome drug resistance to classical chemotherapies, but poor bioavailability and low absorption have limited its clinical use and the mechanisms remain unclear. Also, Adriamycin (Adr) is one of the most active cytotoxic agents in breast cancer; however, the high resistant rate of Adr leads to a poor prognosis. METHODS: We utilized encapsulation in liposomes as a strategy to improve the bioavailability of curcumin and demonstrated that liposomal curcumin altered chemosensitivity of Adr-resistant MCF-7 humanbreast cancer (MCF-7/Adr) by MTT assay. The miRNA and mRNA expression profiles of MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr cells were analyzed by microarray and further confirmed by real-time PCR. We focused on differentially expressed miR-29b-1-5p to explore the involvement of miR-29b-1-5p in the resistance of Adr. Candidate genes of dysregulated miRNAs were identified by prediction algorithms based on gene expression profiles. Networks of KEGG pathways were organized by the selected dysregulated miRNAs. Moreover, protein-protein interaction (PPI) was utilized to map protein interaction networks of curcumin regulated proteins. RESULTS: We first demonstrated liposomal curcumin could rescue part of Adriamycin resistance in breast cancer and further identified 67 differentially expressed microRNAs among MCF-7/S, MCF-7/Adr and curcumin-treated MCF-7/Adr. The results showed that lower expressed miR-29b-1-5p decreased the IC50 of MCF-7/Adr cells and higher expressed miR-29b-1-5p, weaken the effects of liposomal curcumin to Adr-resistance. Besides, we found that 20 target genes (mRNAs) of each dysregulated miRNA were not only predicted by prediction algorithms, but also differentially expressed in the microarray. The results showed that MAPK, mTOR, PI3K-Akt, AMPK, TNF, Ras signaling pathways and several target genes such as PPARG, RRM2, SRSF1and EPAS1, may associate with drug resistance of breast cancer cells to Adr. CONCLUSIONS: We determined that an altered miRNA expression pattern is involved in acquiring resistance to Adr, and that liposomal curcumin could change the resistance to Adr through miRNA signaling pathways in breast cancer MCF-7 cells.