Lentinan mitigates therarubicin-induced myelosuppression by activating bone marrow-derived macrophages in an MAPK/NF-κB-dependent manner.
Bone marrow (BM) suppression (also known as myelosuppression) is the most common and most severe side-effect of therarubicin (THP) and thereby limits the clinical application of this anticancer agent. Lentinan (LNT), a glucan extracted from dried shiitake mushrooms (Lentinula edodes), exhibits a variety of pharmacological activities. The objectives of the present study were to determine the effect of LNT on the myelosuppression of THP-treated mice and to examine the pharmacological mechanism of these effects. In vivo experiments indicated that non-cytotoxic levels of LNT strongly increased blood myeloperoxidase (MPO) activity; improved BM structural injuries; increased the numbers of leukocytes and neutrophils in the blood and BM; elevated the blood levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF); and reduced the self-healing period in THP-treated mice. In vitro experiments indicated that LNT increased the viability of BM-derived macrophages (BMDMs) in a time- and dose-dependent manner without toxic side-effects and markedly increased the release of G-CSF, GM-CSF and M-CSF by BMDMs. Further analyses revealed that LNT activated the NF-κB and MAPK signalling pathways and promoted the nuclear import of p65 and that BAY 11-7082 (a specific inhibitor of NF-κB) suppressed the release of G-CSF, GM-CSF and M-CSF. Furthermore, we found that U0126, SB203580 and SP600125 (specific inhibitors of ERK, p38 and JNK, respectively) markedly inhibited the IKK/IκB/NF-κB-dependent release of G-CSF, GM-CSF and M-CSF. In conclusion, LNT induces the production of G-CSF, GM-CSF and M-CSF by activating the MAPK/NF-κB signalling pathway in BM cells, thereby mitigating THP-induced myelosuppression.
Department of Radiology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Qiang
Q
Liu
Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Lei
L
Dong
Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Hong
H
Li
Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Jia
J
Yuan
Department of Radiology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Yuping
Y
Peng
Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Shejiao
S
Dai
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007912:Lentinan / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology
D000873:Anthracenes; D020672:I-kappa B Proteins; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D016179:Granulocyte Colony-Stimulating Factor; C432165:pyrazolanthrone; D007912:Lentinan; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C027260:pirarubicin; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580