Galimberti S, Canestraro M, Pacini S, Fazzi R, Orciuolo E, Trombi L, Mattii L, Battolla B, Capodanno A, Collecchi P, Veroni F, Simi P, Piaggi S, Casini A, Petrini M
Department of Oncology, Transplant and Advances in Medicine, Section of Hematology, University of Pisa, Ospedale S. Chiara, Via Roma, 56, 56100 Pisa, Italy.
Leuk Res. 2008 Jan;32(1):103-12. doi: 10.1016/j.leukres.2007.05.023. Epub 2007 Jul 16.
PS-341 (Bortezomib) is a dipeptide boronic acid proteasome inhibitor with antitumor activity that induces apoptosis in different human cancer cell lines. We investigated effects of PS-341 (Bortezomib) on cell proliferation, cell cycle progression, induction of apoptosis and differentiation in a megakaryoblastic (MO7-e) cell line. PS-341 was able to retain NF-kappaB in the cytoplasm and inhibit cell growth (IC(50)=22.5 nM), in a dose/time-dependent way. This anti-proliferative activity resulted to be lineage-specific, because other leukemic cell lines (KG1a, K562/R7, HL60/DNR) were unaffected by the PS-341 treatment. Moreover, PS-341 in MO7-e induced a significant pro-apoptotic effect from 10 nM concentration (40% versus 12% in the control, p<0.05). On the other hand, at lower concentration (5 nM), Bortezomib blocked cell cycle in the G2 phase. Finally, this compound was able to down-regulate WT1 expression. No significant effects on cell differentiation were found. Because a spontaneous NF-kappaB activation has been reported in megakaryocytes from patients affected by myeloproliferative disorders, Bortezomib would so be an attractive therapeutic tool for these malignancies, including essential thrombocythemia or idiopathic myelofibrosis. Preliminary data show an inhibiting activity of Bortezomib in the megakaryocytic colonies formation. Finally, also down-regulation of the WT1 gene Bortezomib-driven could be relevant, because of the role that this gene would play in the pathogenesis of acute and chronic myeloproliferative disorders.
PS - 341（硼替佐米）是一种具有抗肿瘤活性的二肽硼酸蛋白酶体抑制剂，可在不同人类癌细胞系中诱导细胞凋亡。我们研究了PS - 341（硼替佐米）对巨核母细胞（MO7 - e）细胞系中细胞增殖、细胞周期进程、凋亡诱导和分化的影响。PS - 341能够使核因子κB保留在细胞质中，并以剂量/时间依赖性方式抑制细胞生长（半数抑制浓度[IC(50)] = 22.5 nM）。这种抗增殖活性具有谱系特异性，因为其他白血病细胞系（KG1a、K562/R7、HL60/DNR）不受PS - 341处理的影响。此外，在MO7 - e细胞中，PS - 341从10 nM浓度起就诱导了显著的促凋亡作用（40%，而对照组为12%，p < 0.05）。另一方面，在较低浓度（5 nM）时，硼替佐米使细胞周期阻滞在G2期。最后，该化合物能够下调WT1表达。未发现对细胞分化有显著影响。由于在骨髓增殖性疾病患者的巨核细胞中已报道有核因子κB的自发激活，硼替佐米因此可能是治疗这些恶性肿瘤（包括原发性血小板增多症或特发性骨髓纤维化）的一种有吸引力的治疗工具。初步数据显示硼替佐米对巨核细胞集落形成有抑制活性。最后，硼替佐米驱动的WT1基因下调也可能具有相关性，因为该基因在急慢性骨髓增殖性疾病的发病机制中所起的作用。
