Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro
Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro
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DOI：
10.1038/sj.leu.2403400
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发表时间：
2004-08-01
期刊：
影响因子：
11.4
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Satou, Y;Nosaka, K;Matsuoka, M
成人t细胞白血病（Adult T-cell leukemia， ATL）是一种来源于cd4阳性t淋巴细胞的致死性肿瘤，无论如何强化化疗，其平均生存时间都不到1年。核因子- kappab （NF-kappaB）活化在HTLV-I相关细胞中被报道，并与肿瘤发生、抗癌药物抵抗和细胞凋亡有关。我们在体外和体内研究了蛋白酶体抑制剂硼替佐米（以前称为PS-341）对ATL细胞的影响。硼替佐米可以抑制ATL细胞中IkappaBalpha的降解，从而在体外抑制ATL细胞NF-kappaB，诱导细胞死亡。对硼替佐米的敏感性与NF-kappaB激活密切相关，表明NF-kappaB通路的抑制与硼替佐米诱导的细胞死亡有关。虽然大多数细胞死亡是凋亡，但在caspase抑制剂z-VAD-fmk存在下观察到坏死细胞死亡。体内给药硼替佐米后，体内肿瘤生长受到抑制，表明硼替佐米对体内ATL细胞有效。这些研究表明，硼替佐米通过诱导ATL细胞凋亡，在体外和体内对ATL细胞都有很高的抑制作用，其临床应用可能会改善ATL患者的预后。
Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T-lymphocytes, and regardless of intensive chemotherapy, its mean survival time is less than 1 year. Nuclear factor-kappaB (NF-kappaB) activation was reported in HTLV-I associated cells, and has been implicated in oncogenesis and resistance to anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor, bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo. Bortezomib could inhibit the degradation of IkappaBalpha in ATL cells, resulting in suppression of NF-kappaB and induction of cell death in ATL cells in vitro. Susceptibilities to bortezomib were well correlated with NF-kappaB activation, suggesting that suppression of the NF-kappaB pathway was implicated in the cell death induced by bortezomib. Although the majority of the cell death was apoptosis, necrotic cell death was observed in the presence of a caspase inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective against ATL cells in vivo. These studies revealed that bortezomib is highly effective against ATL cells in vitro and in vivo by induction of apoptosis, and its clinical application might improve the prognosis of patients with this fatal disease.