Institute of Hematology and Blood Transfusion, U Nemocnice 1,128 20 Prague 2, Czech Republic.
Neoplasma. 2011;58(1):35-44. doi: 10.4149/neo_2011_01_35.
Histone deacetylase inhibitors (HDACi) are emerging new class of anticancer agents that act by inhibiting cell growth, inducing cell cycle arrest and apoptosis of various cancer cells. However, in some conditions, apoptosis can be blocked and non apoptotic cell death and irreversible growth arrest, namely senescence, can be activated as potential tumor-suppressor mechanism. Here we evaluated the dosage effects of HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) in a series of human leukaemia cell lines. We investigated, what concentration of SAHA and VPA can optimally induce apoptosis, growth inhibition or stress-induced premature senescence. We have found that SAHA inhibited proliferation and induced apoptosis in concentration 1000x lower than VPA. The senescence phenotype was preferentially induced by lower dosage of HDACi and required longer incubation time (5 days) while apoptosis was induced by higher dosage and appeared already after 24h. The optimal doses for the induction of cell death are 2,5-5 μM of SAHA and 2,5-5 mM of VPA. These doses of HDACi induce both apoptosis and senescence of studied leukemia cell lines.
组蛋白去乙酰化酶抑制剂（HDACi）是一类新兴的抗癌药物，通过抑制细胞生长、诱导细胞周期停滞和各种癌细胞凋亡来发挥作用。然而，在某些情况下，凋亡可以被阻断，而非凋亡性细胞死亡和不可逆的生长停滞，即衰老，可以被激活作为潜在的肿瘤抑制机制。在这里，我们评估了组蛋白去乙酰化酶抑制剂（SAHA）和丙戊酸（VPA）在一系列人白血病细胞系中的剂量效应。我们研究了哪种浓度的 SAHA 和 VPA 可以最佳地诱导凋亡、生长抑制或应激诱导的过早衰老。我们发现，SAHA 的抑制增殖和诱导凋亡的浓度比 VPA 低 1000 倍。衰老表型优先由较低剂量的 HDACi 诱导，并需要更长的孵育时间（5 天），而凋亡由较高剂量诱导，在 24 小时后出现。诱导细胞死亡的最佳剂量为 2.5-5 μM 的 SAHA 和 2.5-5 mM 的 VPA。这些剂量的 HDACi 诱导研究白血病细胞系的凋亡和衰老。
