Improved Chemotherapeutic Activity by Morus alba Fruits through Immune Response of Toll-Like Receptor 4.

Bo Chang,Mi Lee,Seon Kim,Sung Kim,Hyun Park

doi:10.3390/ijms161024139

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.

Highlights

IntroductionMany cancer chemotherapeutic agents can produce toxicity, which leads to myelosuppression and immunosuppression [1]
Cancer treatment strategies include surgery, chemotherapy, and radiation therapy
Pattern recognition receptors, such as TLR2, TLR4, and TLR6, are involved in the binding of natural products to macrophages, which leads to macrophage activation [16,17]

Summary

Introduction

Many cancer chemotherapeutic agents can produce toxicity, which leads to myelosuppression and immunosuppression [1]. Immune status is important for growth and the combatting of cancer. Enhancement of host immune response has been accepted as a tool for defense against cancer without any side effects. Effective immune enhancement for anti-tumor activity requires antigen presenting cells, T lymphocytes, and natural killer (NK) cells [2,3]. Many candidate cancer chemotherapeutic agents activate significant antigen presenting cells, such as dendritic cells and macrophages, through toll-like receptors (TLRs), which are able to perform antigen uptake, processing and initiation of T cell responses. TLRs are very important in early innate immune defense. The TLR agonists have a potential of tumoricidal activity via TLR-activated innate immune responses.

Results

Discussion

Conclusion