title: Synergistic effect of combinatorial treatment with curcumin and mitomycin C on the induction of apoptosis of breast cancer cells: a cDNA microarray analysis.
abstract: In order to explore the synergistic mechanisms of combinatorial treatment using curcumin and mitomycin C (MMC) for breast cancer, MCF-7 breast cancer xenografts were conducted to observe the synergistic effect of combinatorial treatment using curcumin and MMC at various dosages. The synergistic mechanisms of combinatorial treatment using curcumin and MMC on the inhibition of tumor growth were explored by differential gene expression profile, gene ontology (GO), ingenuity pathway analysis (IPA) and Signal-Net network analysis. The expression levels of selected genes identified by cDNA microarray expression profiling were validated by quantitative RT-PCR (qRT-PCR) and Western blot analysis. Effect of combinatorial treatment on the inhibition of cell growth was observed by MTT assay. Apoptosis was detected by flow cytometric analysis and Hoechst 33258 staining. The combinatorial treatment of 100 mg/kg curcumin and 1.5 mg/kg MMC revealed synergistic inhibition on tumor growth. Among 1501 differentially expressed genes, the expression of 25 genes exhibited an obvious change and a significant difference in 27 signal pathways was observed (p<0.05). In addition, Mapk1 (ERK) and Mapk14 (MAPK p38) had more cross-interactions with other genes and revealed an increase in expression by 8.14- and 11.84-fold, respectively during the combinatorial treatment by curcumin and MMC when compared with the control. Moreover, curcumin can synergistically improve tumoricidal effect of MMC in another human breast cancer MDA-MB-231 cells. Apoptosis was significantly induced by the combinatorial treatment (p<0.05) and significantly inhibited by ERK inhibitor (PD98059) in MCF-7 cells (p<0.05). The synergistic effect of combinatorial treatment by curcumin and MMC on the induction of apoptosis in breast cancer cells may be via the ERK pathway.
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. tazhou@163.com.
authors.forename: Qian-Mei
authors.initials: QM
authors.lastname: Zhou
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. cqlw1975@126.com.
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Chen
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. sbwsyt625@163.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Du
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. xiufengw@sina.com.
authors.forename: Xiu-Feng
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. ava0048@163.com.
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Lu
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. zhanghuiman@126.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. ssb@shutcm.edu.cn.
authors.forename: Shi-Bing
authors.initials: SB
authors.lastname: Su
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D016685:Mitomycin; D003474:Curcumin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one