Fucoidan prevents multiple myeloma cell escape from chemotherapy-induced drug cytotoxicity

Abstract

Minimal residual disease (MRD) occurrence with some chemotherapy drugs that promote tumor cell escape is also a key factor in blood malignancy relapse. We observed that cytarabine promotes multiple myeloma (MM) cell escape and that the number of cells in the lower chamber increased with increasing clinical disease stage in in vitro model which was constructed by a Boyden chamber, matrigel glue and serum from MM patients in different disease stages. The mechanism of cytarabine that promotes MM cell escape is closely associated with the up-regulation of CXCR4. SDF-1α can up-regulate the expression of MMP9 and RHoC proteins in MM cells with up-regulated CXCR4, and further promote the cell escape. Fucoidan, a sulfated polysaccharide in the cell wall matrix of brown algae, has attracted much attention for its multiple biological activities, and we further explored the effects and possible underlying mechanisms of fucoidan on MM cell escape from cytarabine cytotoxicity. The results show that fucoidan may decrease MM cell escape from cytarabine cytotoxicity, and that fucoidan can down-regulate CXCR4, MMP9 and RHoC expression. This research provides new direction for investigating MRD occurrence and prevention.

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.