Nasr Rihab, El-Sabban Marwan E, Karam José-Antonio, Dbaibo Ghassan, Kfoury Youmna, Arnulf Bertrand, Lepelletier Yves, Bex Françoise, de Thé Hugues, Hermine Olivier, Bazarbachi Ali
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Oncogene. 2005 Jan 13;24(3):419-30. doi: 10.1038/sj.onc.1208212.
HTLV-I associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using pharmacological concentrations of the proteasome inhibitor PS-341, we demonstrate inhibition of cell proliferation and induction of apoptosis in fresh ATL cells, HTLV-I transformed and HTLV-I-negative malignant T cells, while normal resting or activated T lymphocytes were resistant. Combination of PS-341 and doxorubicin or etoposide resulted in an additive growth inhibition. In HTLV-I-negative malignant cells, PS-341 treatment significantly downregulated the antiapoptotic protein X-IAP and to a lesser extent c-IAP-1 and bcl-X(L) and resulted in caspase-dependent apoptosis. In HTLV-I transformed cells, the inhibition of the proteasomal degradation of Tax by PS-341 likely explains the relative protection of HTLV-I infected cells against caspase-dependent apoptosis. PS-341 treatment of these cells stabilized IkappaBalpha, IkappaBbeta, IkappaBvarepsilon, p21, p27 and p53 proteins and selectively inhibited Rel-A DNA binding NF-kappaB complexes. In both HTLV-I-positive and -negative cells, PS-341 treatment induced ceramide accumulation that correlated with apoptosis. We conclude that PS-341 affects multiple pathways critical for the survival of HTLV-I-positive and -negative malignant T cells supporting a potential therapeutic role for PS-341 in both ATL and HTLV-I-negative T-cell lymphomas, whether alone or in combination with chemotherapy.
人嗜T淋巴细胞病毒I型（HTLV-I）相关的成人T细胞白血病（ATL）和HTLV-I阴性外周T细胞淋巴瘤预后较差。使用蛋白酶体抑制剂PS-341的药理浓度，我们证明其可抑制新鲜ATL细胞、HTLV-I转化的和HTLV-I阴性恶性T细胞的细胞增殖并诱导其凋亡，而正常静息或活化的T淋巴细胞具有抗性。PS-341与阿霉素或依托泊苷联合使用可产生相加性生长抑制作用。在HTLV-I阴性恶性细胞中，PS-341处理可显著下调抗凋亡蛋白X-IAP，对c-IAP-1和bcl-X(L)的下调程度较小，并导致半胱天冬酶依赖性凋亡。在HTLV-I转化细胞中，PS-341对Tax蛋白酶体降解的抑制作用可能解释了HTLV-I感染细胞对半胱天冬酶依赖性凋亡的相对保护作用。用PS-341处理这些细胞可使IkappaBalpha、IkappaBbeta、IkappaBvarepsilon、p21、p27和p53蛋白稳定，并选择性抑制Rel-A DNA结合NF-kappaB复合物。在HTLV-I阳性和阴性细胞中，PS-341处理均诱导神经酰胺积累，且与凋亡相关。我们得出结论，PS-341影响HTLV-I阳性和阴性恶性T细胞存活所必需的多种途径，这支持PS-341在ATL和HTLV-I阴性T细胞淋巴瘤中无论是单独使用还是与化疗联合使用都具有潜在治疗作用。
