Fucoidan prevents multiple myeloma cell escape from chemotherapy-induced drug cytotoxicity
Graphical abstract
Introduction
Multiple myeloma is an incurable B-cell neoplasm characterized by clonal plasma cell expansion that originates from the hematopoietic bone marrow. Relapse caused by minimal residual disease is also a key factor for failure [1], [2]. Thus, it is necessary to explore the mechanism of MRD development and to determine effective methods to reduce MRD occurrence.
Recent studies showed [3], [4] that some chemotherapy drugs stimulate tumor cells to activate their protection system and to move to safe areas to avoid the toxic effect of chemotherapy; this could result in the development of MRD. Kato [5] found that cytarabine therapy could lead to neoplastic cell escape to a bone marrow (BM) niche or to portal areas, and confirmed that the neoplastic cells are closely connected to the SDF-1/CXCR4 axis. The SDF-1/CXCR4 axis is involved in stem cell mobilization or homing and in cancer metastasis and invasion, but it also plays an important role [6], [7]. In this research, we have demonstrated that cytarabine can promote MM cell escape and that the SDF-1/CXCR4 axis, RHoC and MMP9 proteins play important roles in the escape process. Thus, blocking the SDF-1/CXCR4 axis or down-regulating RHoC and MMP9 protein expression may become an effective target for reducing MM cell escape during cytarabine cytotoxic therapy.
Fucoidan, which is a sulfated polysaccharide found in edible brown algae, has attracted much attention for its multiple biological activities [8], [9]. It has been shown that fucoidan regulates the SDF-1/CXCR4 axis, and inhibits cancer cell migration and invasion [10], [11]. The objective of our study is to determine if the SDF-1/CXCR4 axis is involved in the mechanism by which fucoidan reduces MM cell escape in response to cytotoxic cytarabine therapy.
Section snippets
Cells and reagents
The human myeloma cell line (RPMI8226) was obtained from the Shanghai Cell Bank, China. The human myeloma cell line (U266) was a gift from the Beijing Cancer Cell Bank, China. Fetal bovine serum was purchased from Sijiqing Company (Hangzhou Chinese), fucoidan was purchased from Sigma Systems, and cytarabine was obtained from Pfizer. The Boyden chamber was purchased from Millipore, matrigel was purchased from BD Pharmingen, and the apoptosis kit was purchased from Keygen Biotech (Nanjing
SDF-1 expression in MM patients and healthy volunteers
ELISA was used to evaluate serum SDF-1 levels in MM patients and in healthy volunteers. We selected serum from 47 MM patients and 12 healthy volunteers. As shown in Table 1, the mean serum concentration was 1.77 ± 0.05 ng/ml in stage I, 2.22 ± 0.18 ng/ml in stage II, 2.80 ± 0.13 ng/ml in stage III, and 1.71 ± 0.08 ng/ml in healthy volunteers.
Effect of fucoidan on preventing MM cell escape from cytarabine cytotoxicity
Serum from MM patients at different disease stages, and a Boyden chamber with matrigel glue was used to construct the migration and invasion model to study the
Discussion
Relapse is one of the leading causes of MM treatment failure. Current studies of MRD have focused mainly on improving methods to detect MRD, while the mechanism of MRD occurrence remains poorly understood. Some chemotherapy drugs can promote tumor cell escape and MRD occurrence, and our study confirmed that cytarabine can promote MM cell escape. We also found that prophylactic use of fucoidan reduced cytarabine-induced MM cell escape effectively through the stimulation of the SDF-1/CXCR4 axis,
Acknowledgments
We would like to thank Wei-xue Tang, Fan Jiang, Yu-mei Tian for their excellent technical assistance. This work was supported by the Chongqing Medical University Neurology Derangement Lab.
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