title: Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4.
abstract: Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, Korea. oama611@nate.com.
authors.forename: Bo Yoon
authors.initials: BY
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea. suntiger85@hanmail.net.
authors.forename: Seon Beom
authors.initials: SB
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea. mklee@chungbuk.ac.kr.
authors.forename: Mi Kyeong
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Institute of Zoonosis Research Center and Department Infection Biology, College of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Korea. hyunpk@wonkwang.ac.kr.
authors.forename: Hyun
authors.initials: H
authors.lastname: Park
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, Korea. sungykim@wonkwang.ac.kr.
authors.forename: Sung Yeon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D005638:Fruit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D031625:Morus / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D010936:Plant Extracts / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000970:Antineoplastic Agents; D005472:Fluorouracil; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009569:Nitric Oxide; D010936:Plant Extracts; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse
keywords: 5-fluorouracil (5-FU); Morus alba fruits; TLR; chemotherapeutic activity; immune response