Homoharringtonine enhances bortezomib antimyeloma activity in myeloma cells adhesion to bone marrow stromal cells and in SCID mouse xenografts
Homoharringtonine enhances bortezomib antimyeloma activity in myeloma cells adhesion to bone marrow stromal cells and in SCID mouse xenografts
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DOI：
10.1016/j.leukres.2017.04.007
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发表时间：
2017-06-01
影响因子：
2.7
通讯作者：
Huang, Huifang
中科院分区：
文献类型：
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作者：
Chen, Ping;Yuan, Qin;Huang, Huifang
尽管多发性骨髓瘤（multiple myeloma，MM）的治疗取得了很大的进展，但MM仍然是一种无法治愈的疾病。硼替佐米（BTZ）是一种可逆的26 S蛋白酶体抑制剂，对MM非常有效，但不能根除骨髓龛中的MM细胞，最终导致疾病复发。高三尖杉酯碱（HHT）是一种已知的抗白血病药物，在体外和体内都能抑制MM。本研究旨在研究HHT是否可以增强BTZ在与骨髓基质细胞共培养的MM细胞和体内异种移植模型中的抗肿瘤活性。我们发现，骨髓瘤细胞与人基质细胞系的共培养显著降低了骨髓瘤细胞对BTZ治疗的敏感性。HHT抑制MM细胞的增殖和增强BTZ的抗骨髓瘤作用的抑制典型和非典型NF-？B途径。HHT还增强BTZ在体内异种移植模型中的抗骨髓瘤作用。综上所述，我们的数据表明，HHT可以增强BTZ的抗骨髓瘤活性在体外和体内，这可能是一个新的临床治疗MM。
Despite the great progress in the treatment, multiple myeloma (MM) still remains incurable. Bortezomib (BTZ), a reversible inhibitor of the 26S proteasome, is very effective against MM but unable to eradicate the MM cells in bone marrow niche eventually causing the disease relapse. Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits MM both in vitro and in vivo. This study aimed to investigate whether HHT could potentiate the anti-tumor activity of BTZ in MM cells cocultured with bone marrow stromal cells and in vivo xenograft models. We found that coculture of myeloma cells with a human stroma cell line significantly decreased the sensitivity of myeloma cells to BTZ treatment. HHT inhibited the proliferation of MM cells and potentiated the anti-myeloma effects of BTZ by inhibition of both canonical and noncanonical NF-?B pathways. HHT also enhanced the anti-myeloma effect of BTZ in vivo xenograft models. Taken together, our data suggest that HHT can enhance the anti-myeloma activity of BTZ both in vitro and in vivo, which may represent a new clinical treatment in MM.