title: Synergistic enhancement of cancer therapy using a combination of ceramide and docetaxel.
abstract: Ceramide (CE)-based combination therapy (CE combination) as a novel therapeutic strategy has attracted great attention in the field of anti-cancer therapy. The principal purposes of this study were to investigate the synergistic effect of CE in combination with docetaxel (DTX) (CE + DTX) and to explore the synergy mechanisms of CE + DTX. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and combination index (CI) assay showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on murine malignant melanoma cell (B16, CI = 0.31) and human breast carcinoma cell (MCF-7, CI = 0.48). The apoptosis, cell cycle, and cytoskeleton destruction study demonstrated that CE could target and destruct the microfilament actin, subsequently activate Caspase-3 and induce apoptosis. Meanwhile, DTX could target and disrupt the microtubules cytoskeleton, leading to a high proportion of cancer cells in G2/M-phase arrest. Moreover, CE plus DTX could cause a synergistic destruction of cytoskeleton, which resulted in a significantly higher apoptosis and a significantly higher arrest in G2/M arrest comparing with either agent alone (p < 0.01). The in vivo antitumor study evaluated in B16 tumor-bearing mice also validated the synergistic effects. All these results suggested that CE could enhance the antitumor activity of DTX in a synergistic manner, which suggest promising application prospects of CE + DTX combination treatment.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 West Culture Road, Ji'nan 250012, China. fenglixia0910@126.com.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 West Culture Road, Ji'nan 250012, China. sdlimin@sina.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 West Culture Road, Ji'nan 250012, China. o-oliuyongjun@163.com.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 West Culture Road, Ji'nan 250012, China. yangshaomei01@163.com.
authors.forename: Shao-Mei
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 West Culture Road, Ji'nan 250012, China. zhangnancy9@sdu.edu.cn.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D002518:Ceramides; D043823:Taxoids; D000077143:Docetaxel; D053148:Caspase 3