title: SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice.
abstract: Chemotherapy and immunotherapy are the main remedies used in cancer treatment. Because immunotherapy can not only reduce the toxicity of chemotherapeutics but also enhance antitumor effects in vivo, combining these two therapies is a trend that continues to gain more attention in clinic. SEP, a polysaccharide isolated from Strongylocentrotus nudus egg, has been reported to display antitumor activity by stimulating immune cells, including NK and T cells, via TLR2 and TLR4. In the present study, the synergistic effect between SEP and 5-fluorouracil (5-FU), a traditional cytotoxic drug, in vitro and in vivo was investigated. The results obtained indicated that SEP alone stimulated NK-92 cytotoxicity and coordinated with 5-FU to augment the cytotoxicity of NK-92 cells against HepG-2 or A549 cells in vitro. SEP promoted NK-92 activity by stimulating NKG2D and its downstream DAP10/PI3K/Erk signaling pathway. Additionally, 5-FU could increase MICA expression on HepG-2 or A549 cells and prevent membrane MICA from shedding as soluble MICA, which were abrogated in the tumor cells transfected with ADAM 10 overexpression plasmid. Moreover, in H22- or Lewis lung cancer (LLC)-bearing mouse models, SEP reversed 5-FU-induced atrophy and apoptosis in both the spleen and bone marrow in vivo by suppressing ROS generation and caspase-3 activation. All of these results highlight the potential for the combination of SEP and 5-FU in cancer therapy in the future.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.|Research Institute of Advanced Surgical Techniques and Engineering of Xi'an Jiaotong University, Regenerative Medicine and Surgery Engineering Research Center of Shaanxi Province, First Affiliated Hospital, Xi'an Jiaotong University, Shaanxi, Xi'an, 710061, PR China.
authors.forename: Mengyun
authors.initials: M
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Rui Jin Hospital, Research Institute of Pancreatic Diseases, School of Medicine, Shanghai JiaoTong University, Shanghai, 200025, PR China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dou
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
authors.affiliation: Department of General Surgery, Rui Jin Hospital, Research Institute of Pancreatic Diseases, School of Medicine, Shanghai JiaoTong University, Shanghai, 200025, PR China.
authors.forename: Baiyong
authors.initials: B
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, 210009, PR China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000072283:A549 Cells; D000072197:ADAM10 Protein / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011134:Polysaccharides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D047269:Strongylocentrotus / Q000737:chemistry; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011134:Polysaccharides; D017382:Reactive Oxygen Species; D053829:Amyloid Precursor Protein Secretases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D005472:Fluorouracil
keywords: 5-fluorouracil; SEP; antitumor activity; apoptosis; immunotherapy