Abou-Merhi R, Khoriaty R, Arnoult D, El Hajj H, Dbouk H, Munier S, El-Sabban M E, Hermine O, Gessain A, de Thé H, Mahieux R, Bazarbachi A
Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
Leukemia. 2007 Aug;21(8):1792-801. doi: 10.1038/sj.leu.2404797. Epub 2007 Jun 14.
Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.
卡波西肉瘤（KS）相关疱疹病毒（KSHV）是原发性渗出性淋巴瘤和KS的病原体。原发性渗出性淋巴瘤（PEL）是B细胞的侵袭性增殖。传统化疗对PEL患者的益处有限，预后很差。我们之前报道，用三氧化二砷（As）联合α干扰素（IFN-α）或硼替佐米（PS-341）蛋白酶体抑制剂治疗人类1型T细胞白血病病毒（HTLV-1）相关的成人T细胞白血病/淋巴瘤细胞会诱导细胞周期停滞和凋亡，部分原因是组成型核因子-κB（NF-κB）激活的逆转。PEL细胞也表现出激活的NF-κB途径，这对其存活是必需的。这促使我们研究PS-341或As/IFN-α组合对PEL细胞的影响。在PS-341和As/IFN-α处理的细胞中观察到细胞增殖的显著抑制和凋亡的诱导。这与线粒体膜电位的消散、细胞色素c的胞质释放、半胱天冬酶激活相关，并且被z-VAD半胱天冬酶抑制剂逆转。PS-341和As/IFN-α处理消除了NF-κB向细胞核的易位，并降低了抗凋亡蛋白Bcl-XL的水平。总之，这些结果为未来在PEL患者中使用PS-341或联合使用As和IFN-α提供了合理的治疗依据。
