Lentinan mitigates therarubicin-induced myelosuppression by activating bone marrow-derived macrophages in an MAPK/NF-κB-dependent manner

Liu,Qiang; Dong,Lei; Li,Hong; Yuan,Jia; Peng,Yuping; Dai,Shejiao

doi:10.3892/or.2016.4769

Lentinan mitigates therarubicin-induced myelosuppression by activating bone marrow-derived macrophages in an MAPK/NF-κB-dependent manner

Authors:
- Qiang Liu
- Lei Dong
- Hong Li
- Jia Yuan
- Yuping Peng
- Shejiao Dai
View Affiliations

Affiliations: Department of Radiology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: April 26, 2016 https://doi.org/10.3892/or.2016.4769
Pages: 315-323

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, et al: Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: The THP Monotherapy Study Group Trial. J Clin Oncol. 31:1422–1427. 2013. View Article : Google Scholar : PubMed/NCBI
2	Tomita N, Kodama F, Tsuyama N, Sakata S, Takeuchi K, Ishibashi D, Koyama S, Ishii Y, Yamamoto W, Takasaki H, et al: Biweekly THP-COP therapy for newly diagnosed peripheral T-cell lymphoma patients. Hematol Oncol. 33:9–14. 2015. View Article : Google Scholar
3	Shimomura Y, Baba R, Watanabe A, Horikoshi Y, Asami K, Hyakuna N, Iwai A, Matsushita T, Yamaji K, Hori T, et al Japanese Childhood Cancer and Leukemia Study Group (JCCLSG): Assessment of late cardiotoxicity of pirarubicin (THP) in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 57:461–466. 2011. View Article : Google Scholar : PubMed/NCBI
4	Li Y, Tang JH, Huang XE and Li CG: Clinical comparison on the safety and efficacy of fluorouracil/pirarubicin/cyclophosphamide (FPC) with fluorouracil/epirubicin/cyclophosphamide (FEC) as postoperative adjuvant chemotherapy in breast cancer. Asian Pac J Cancer Prev. 12:1795–1798. 2011.
5	du Bois A, Meerpohl HG, Madjar H, Spinner D, Dall P, Pfisterer J and Bauknecht T: phase II study of pirarubicin combined with cisplatin in recurrent ovarian cancer. J Cancer Res Clin Oncol. 120:173–178. 1994. View Article : Google Scholar : PubMed/NCBI
6	Zhao H, Yao Y, Wang Z, Lin F, Sun Y and Chen P: Therapeutic effect of pirarubicin-based chemotherapy for osteosarcoma patients with lung metastasis. J Chemother. 22:119–124. 2010. View Article : Google Scholar : PubMed/NCBI
7	Hyun SY, Cheong JW, Kim SJ, Min YH, Yang DH, Ahn JS, Lee WS, Ryoo HM, Do YR, Lee HS, et al: High-dose etoposide plus granulocyte colony-stimulating factor as an effective chemomobilization regimen for autologous stem cell transplantation in patients with non-Hodgkin Lymphoma previously treated with CHOP-based chemotherapy: A study from the Consortium for Improving Survival of Lymphoma. Biol Blood Marrow Transplant. 20:73–79. 2014. View Article : Google Scholar
8	Asakuma M, Yamamoto M, Wada M, Ryuge S, Katono K, Yokoba M, Fukui T, Takakura A, Otani S, Maki S, et al: Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer. Cancer Chemother Pharmacol. 69:1529–1536. 2012. View Article : Google Scholar : PubMed/NCBI
9	Gudi R, Krishnamurthy M and Pachter BR: Astemizole in the treatment of granulocyte colony-stimulating factor-induced bone pain. Ann Intern Med. 123:236–237. 1995. View Article : Google Scholar : PubMed/NCBI
10	Chihara G, Hamuro J, Maeda YY, Shiio T, Suga T, Takasuka N and Sasaki T: Antitumor and metastasis-inhibitory activities of lentinan as an immunomodulator: An overview. Cancer Detect Prev Suppl. 1:423–443. 1987.PubMed/NCBI
11	Liu YH, Ma SD, Fu QJ, Zhao LY, Li Y, Wang HQ and Li MC: Effect of lentinan on membrane-bound protein expression in splenic lymphocytes under chronic low-dose radiation. Int Immunopharmacol. 22:505–514. 2014. View Article : Google Scholar : PubMed/NCBI
12	Attia SM, Harisa GI, Abd-Allah AR, Ahmad SF and Bakheet SA: The influence of lentinan on the capacity of repair of DNA damage and apoptosis induced by paclitaxel in mouse bone marrow cells. J Biochem Mol Toxicol. 27:370–377. 2013. View Article : Google Scholar : PubMed/NCBI
13	Joo SY, Song YA, Park YL, Myung E, Chung CY, Park KJ, Cho SB, Lee WS, Kim HS, Rew JS, et al: Epigallocatechin-3-gallate inhibits LPS-induced NF-κB and MAPK signaling pathways in bone marrow-derived macrophages. Gut Liver. 6:188–196. 2012. View Article : Google Scholar : PubMed/NCBI
14	Li X, Liu Y, Wang L, Li Z and Ma X: Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells. Immunobiology. 220:399–405. 2015. View Article : Google Scholar
15	Mannello F, Ligi D, Canale M and Raffetto JD: Sulodexide down-regulates the release of cytokines, chemokines, and leukocyte colony stimulating factors from human macrophages: Role of glycosaminoglycans in inflammatory pathways of chronic venous disease. Curr Vasc Pharmacol. 12:173–185. 2014. View Article : Google Scholar
16	Lee KY, Suh BG, Kim JW, Lee W, Kim SY, Kim YY, Lee J, Lim J, Kim M, Kang CS, et al: Varying expression levels of colony stimulating factor receptors in disease states and different leukocytes. Exp Mol Med. 32:210–215. 2000. View Article : Google Scholar
17	Kamezaki K, Shimoda K, Numata A, Haro T, Kakumitsu H, Yoshie M, Yamamoto M, Takeda K, Matsuda T, Akira S, et al: Roles of Stat3 and ERK in G-CSF signaling. Stem Cells. 23:252–263. 2005. View Article : Google Scholar : PubMed/NCBI
18	Davis BK: Isolation, culture, and functional evaluation of bone marrow-derived macrophages. Methods Mol Biol. 1031:27–35. 2013. View Article : Google Scholar : PubMed/NCBI
19	Salva S, Marranzino G, Villena J, Agüero G and Alvarez S: Probiotic Lactobacillus strains protect against myelosuppression and immunosuppression in cyclophosphamide-treated mice. Int Immunopharmacol. 22:209–221. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zheng SE, Xiong S, Lin F, Qiao GL, Feng T, Shen Z, Min DL, Zhang CL and Yao Y: Pirarubicin inhibits multidrug-resistant osteosarcoma cell proliferation through induction of G2/M phase cell cycle arrest. Acta Pharmacol Sin. 33:832–838. 2012. View Article : Google Scholar : PubMed/NCBI
21	Munck JN, Rougier P, Chabot GG, Ramirez LH, Bognel C, Lumbroso J, Herait P, Elias D, Lasser P and Gouyette A: Phase I and pharmacological study of intra-arterial hepatic administration of pirarubicin in patients with advanced hepatic metastases. Eur J Cancer. 30A:289–294. 1994. View Article : Google Scholar : PubMed/NCBI
22	Baldo BA: Side effects of cytokines approved for therapy. Drug Saf. 37:921–943. 2014. View Article : Google Scholar : PubMed/NCBI
23	Ina K, Kataoka T and Ando T: The use of lentinan for treating gastric cancer. Anticancer Agents Med Chem. 13:681–688. 2013. View Article : Google Scholar :
24	Fehér J, Chihara G, Vallent K, Deák G, Blázovics A, Gergely P and Kaneko Y: Effect of lentinan on superoxide dismutase enzyme activity in vitro. Immunopharmacol Immunotoxicol. 11:55–61. 1989. View Article : Google Scholar : PubMed/NCBI
25	Sridhar KS, Hussein AM, Benedetto P, Ardalan B, Savaraj N and Richman SP: Phase II trial of 4′-0-tetrahydropyranyladriamycin (pirarubicin) in head and neck carcinoma. Cancer. 70:1591–1597. 1992. View Article : Google Scholar : PubMed/NCBI
26	Kleeberg UR, Reichel L, Wander HE, Beyer JH, Essers U, Fiebig HH and Edler L: Phase II study of pirarubicin in metastatic breast cancer. Onkologie. 13:175–179. 1990.PubMed/NCBI
27	Rapoport BL and Falkson G: phase II clinical study of pirarubicin in hormone resistant prostate cancer. Invest New Drugs. 10:119–121. 1992. View Article : Google Scholar : PubMed/NCBI
28	Wang H, Wang M, Chen J, Tang Y, Dou J, Yu J, Xi T and Zhou C: A polysaccharide from Strongylocentrotus nudus eggs protects against myelosuppression and immunosuppression in cyclophosphamide-treated mice. Int Immunopharmacol. 11:1946–1953. 2011. View Article : Google Scholar : PubMed/NCBI
29	Yu Q, Nie SP, Wang JQ, Liu XZ, Yin PF, Huang DF, Li WJ, Gong DM and Xie MY: Chemoprotective effects of Ganoderma atrum polysaccharide in cyclophosphamide-induced mice. Int J Biol Macromol. 64:395–401. 2014. View Article : Google Scholar
30	Bhatia S, Rathee P, Sharma K, Chaugule BB, Kar N and Bera T: Immuno-modulation effect of sulphated polysaccharide (porphyran) from Porphyra vietnamensis. Int J Biol Macromol. 57:50–56. 2013. View Article : Google Scholar : PubMed/NCBI
31	Xu X, Pan C, Zhang L and Ashida H: Immunomodulatory beta-glucan from Lentinus edodes activates mitogen-activated protein kinases and nuclear factor-kappaB in murine RAW 264.7 macrophages. J Biol Chem. 286:31194–31198. 2011. View Article : Google Scholar : PubMed/NCBI