Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir
Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir
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DOI：
10.1182/blood-2005-02-0735
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发表时间：
2006-01-15
期刊：
影响因子：
20.3
通讯作者：
Yamamoto, N
中科院分区：
文献类型：
--
作者：
Dewan, MZ;Uchihara, J;Yamamoto, N
成人 T 细胞白血病 (ATL) 是一种与人类 T 细胞白血病病毒 I 型 (HTLV-I) 感染相关的 CD4(+) T 细胞侵袭性恶性肿瘤，由于白血病细胞对包括化疗在内的任何常规治疗方案具有抵抗力，因此预后非常差。我们检查了利托那韦（一种 HIV 蛋白酶抑制剂）对 HTLV-I 感染的 T 细胞系和原代 ATL 细胞的作用，发现它诱导细胞凋亡并抑制这些细胞中 NF-κ B 的转录激活。此外，利托那韦还能抑制 NF-κ B 靶标 Bcl-X-L、生存素、c-Myc 和细胞周期蛋白 D2 的表达。在非肥胖糖尿病/严重联合免疫缺陷 (NOD/SCID)/gamma c(null) (NOG) 小鼠中，利托那韦非常有效地阻止 NOG 各个器官中的肿瘤生长和白血病浸润。 小鼠的剂量与治疗艾滋病患者的剂量相同。我们的数据表明，利托那韦具有有效的抗 NF-κB 和抗肿瘤作用，可能在临床上适用于 ATL 的治疗。这些结果也将为白血病和实体瘤的新药开发提供新的理念和新的平台。
Adult T-cell leukemia (ATL), an aggressive malignancy of CD4(+) T cells associated with human T-cell leukemia virus type I (HTLV-I) infection, carries a very poor prognosis because of the resistance of leukemic cells to any conventional regimen, including chemotherapy. We examined the effect of ritonavir, an HIV protease inhibitor, on HTLV-I-infected T-cell lines and primary ATL cells and found that it induced apoptosis and inhibited transcriptional activation of NF-kappa B in these cells. Furthermore, ritonavir inhibited expression of Bcl-X-L, survivin, c-Myc, and cyclin D2, the targets of NF-kappa B. In nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gamma c(null) (NOG) mice, ritonavir very efficiently prevented tumor growth and leukemic infiltration in various organs of NOG mice at the same dose used for treatment of patients with AIDS. Our data indicate that ritonavir has potent anti-NF-kappa B and antitumor effects and might be clinically applicable for treatment of ATL. These results would provide a new concept and novel platform for new drug development of leukemia and solid cancer as well.