Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Mol Cancer Ther. 2011 Nov;10(11):2052-61. doi: 10.1158/1535-7163.MCT-11-0365. Epub 2011 Sep 1.
The ceramide/sphingosine-1-phosphate (S1P) rheostat has been hypothesized to play a critical role in regulating tumor cell fate, with elevated levels of ceramide inducing death and elevated levels of S1P leading to survival and proliferation. Ceramidases are key enzymes that control this rheostat by hydrolyzing ceramide to produce sphingosine and may also confer resistance to drugs and radiation. Therefore, ceramidase inhibitors have excellent potential for development as new anticancer drugs. In this study, we identify a novel ceramidase inhibitor (Ceranib-1) by screening a small molecule library and describe the synthesis of a more potent analogue (Ceranib-2). In a cell-based assay, both compounds were found to inhibit cellular ceramidase activity toward an exogenous ceramide analogue, induce the accumulation of multiple ceramide species, decrease levels of sphingosine and S1P, inhibit the proliferation of cells alone and in combination with paclitaxel, and induce cell-cycle arrest and cell death. In vivo, Ceranib-2 was found to delay tumor growth in a syngeneic tumor model without hematologic suppression or overt signs of toxicity. These data support the selection of ceramidases as suitable targets for anticancer drug development and provide the first nonlipid inhibitors of human ceramidase activity.
神经酰胺/鞘氨醇-1-磷酸（S1P）变阻器被假设在调节肿瘤细胞命运中发挥关键作用，其中神经酰胺水平升高诱导细胞死亡，而 S1P 水平升高则导致细胞存活和增殖。神经酰胺酶是通过水解神经酰胺产生鞘氨醇来控制这个变阻器的关键酶，并且还可能赋予对药物和辐射的抗性。因此，神经酰胺酶抑制剂具有作为新型抗癌药物开发的巨大潜力。在这项研究中，我们通过筛选小分子文库鉴定出一种新型神经酰胺酶抑制剂（Ceranib-1），并描述了更有效的类似物（Ceranib-2）的合成。在基于细胞的测定中，这两种化合物都被发现抑制细胞对外源性神经酰胺类似物的神经酰胺酶活性，诱导多种神经酰胺物质的积累，降低鞘氨醇和 S1P 的水平，单独和与紫杉醇联合抑制细胞增殖，并诱导细胞周期停滞和细胞死亡。在体内，Ceranib-2 在同种异体肿瘤模型中被发现延迟肿瘤生长，而没有血液学抑制或明显的毒性迹象。这些数据支持将神经酰胺酶作为抗癌药物开发的合适靶标，并提供了第一种非脂质的人神经酰胺酶活性抑制剂。
