Bioactive Sialoglycosphingolipids(Gangliosides) and Their Related Amphipathic Sialoglycocompounds:Fundamental Studies and Applications of Anti-Leukemic(Differentiation-Inducing) Activities

我们最近发现，特定的神经节苷脂分子在人髓性白血病细胞系HL-60细胞的分化调控中起重要作用。神经节苷脂GM 3在12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导HL-60细胞向单核细胞分化时呈特征性增高，可诱导HL-60细胞向单核细胞分化;而新乳系神经节苷脂在视黄酸（RA）或二甲基亚砜（DMSO）诱导HL-60细胞向粒细胞分化时呈特征性增高，能诱导HL-60细胞向粒系分化。这些发现提出了这样的可能性：除了神经节苷脂之外，某些类型的含有唾液酸的两亲化合物在添加到培养基中时可能能够诱导HL-60细胞分化。在这种情况下，我们研究了唾液酸胆固醇的分化诱导活性，这是合成的两亲性 ...更多信息 含有唾液酸的糖化合物。结果表明，α-唾液酸胆固醇是HL-60细胞向粒细胞分化的有效诱导剂，其诱导活性具有立体特异性，即α-唾液酸胆固醇的诱导活性远强于β-异头体，细胞的分化依赖于α-唾液酸胆固醇的浓度，并伴有细胞生长抑制。另一种两亲性唾液酸化合物，α-唾液酸甘油酯，也被证明是相当有效的诱导人骨髓性白血病细胞。需要对各种类型的合成唾液酸化合物进行进一步的研究，以阐明在HL-60细胞中诱导分化以及确定分化方向中的结构-活性关系，然而，可以肯定的是，这些唾液酸化合物，α-唾液酸胆固醇和α-唾液酸甘油酯，是抗白血病分化的最佳候选者诱导药物与天然的和合成的唾液酸化合物相似，因为它们被发现比预期的毒性小得多。少

We have recently demonstrated that the particular ganglioside molecules play an important role in regulation of differentiation of human myelogenous leukemia cell line HL-60 cells. The ganglio-series ganglioside GM3, which increases characteristically during monocytic differentiation of HL-60 cells induced by 12-O-tetradecanoyl phorbol-13-acetate (TPA), can induce monocytic differentiation of HL-60 cells, whereas neolacto-series gangliosides, which increase characteristically during granulocytic differentiation of HL-60cells induced by retinoic acid (RA) or dimethylsulfoxide (DMSO), can induce granulocytic differentiation of HL-60 cells. These findings raise the possibility that, in addition to gangliosides, certain types of amphipathic compounds containing sialic acid might be capable of inducing the differentiation of HL-60 cells when added to the culture medium. In this context, we investigated the differentiation-inducing activity of sialocholesterols, which are synthetic amphipath … More ic glycocompounds containing sialic acid. We found that alpha-sialo-cholesterol was a potent inducer for granulocytic differentiation of HL-60 cells, and that the differentiation-inducing activity was stereospecific; that is, alpha-sialocholesterol was much more potent than beta-anomer.The differentiation of cells was dependent on the concentration of alpha-sialocholesterol and accompanied with inhibition of cell growth. Another amphipathic sialocompound, alpha-sialoglyceride, was also demonstrated to be considerably potent for inducing human myelogenous leukemia cells. Further studies with various types of synthetic sialocompounds will be needed to elucidate the structure-activity relationships in the differentiation-induction as well as the determination of differentiation-direction in HL-60 cells however, it will be certain that these sialocompounds, alpha-sialocholesterol and alpha-sialoglyceride, are best candidates ever known for anti-leukemic differentiation-inducing drugs amooth natural and synthetic sialocompounds since they were found to be much less toxic than anticipated. Less