Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells.
Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells.
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作者：
Cain JE;McCaw A;Jayasekara WS;Rossello FJ;Marini KD;Irving AT;Kansara M;Thomas DM;Ashley DM;Watkins DN
组蛋白脱乙酰酶抑制剂 (HDACi) 在近四十年前因其诱导细胞分化的能力而被识别。然而，这些化合物作为癌症疗法的临床开发重点关注它们在血液和淋巴恶性肿瘤中诱导细胞凋亡的能力，通常与常规细胞毒性药物联合使用。在许多情况下，诱导这些作用所需的 HDACi 剂量会导致显着的毒性。由于骨肉瘤细胞响应 DNA 甲基转移酶抑制剂而表达终末成骨细胞分化的标记物，因此我们推断 HDACi 的表观遗传重编程能力可能可用于治疗益处。在这里，我们发现骨肉瘤细胞连续暴露于低浓度的 HDACi LBH589（Panobinostat）三周内会诱导终末成骨细胞分化和不可逆的衰老，而不诱导细胞死亡。值得注意的是，转录分析显示，除了成熟成骨细胞标志物的显着上调外，HDACi 疗法还启动了软骨细胞和脂肪细胞谱系特征的基因特征。在小鼠异种移植模型中，连续低剂量LBH589治疗可诱导持续的细胞抑制反应，同时诱导成熟的成骨细胞基因表达。这些数据表明，骨肉瘤细胞响应 HDACi 治疗而具有显着的分化能力，可在不诱导全身毒性的情况下获得治疗益处。
Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity.
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