Izmir Institute of Technology, Science Faculty, Department of Molecular Biology and Genetics, Urla, 35430, Izmir Turkey.
Curr Med Chem. 2013;20(1):108-22.
Sphingolipids are a class of lipids that have important functions in a variety of cellular processes such as, differentiation, proliferation, senescence, apoptosis and chemotherapeutic resistance. The most widely studied bioactive shingolipids include ceramides, dihydroceramide (dhCer), ceramide-1-phosphate (C1P), glucosyl-ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P). Although the length of fatty acid chain affects the physiological role, ceramides and sphingosine are known to induce apoptosis whereas C1P, S1P and GluCer induce proliferation of cells, which causes the development of chemoresistance. Previous studies have implicated the significance of bioactive shingolipids in oncogenesis, cancer progression and drug- and radiation-resistance. Therefore, targeting the elements of sphingolipid metabolism appears important for the development of novel therapeutics or to increase the effectiveness of the current treatment strategies. Some approaches involve the development of synthetic ceramide analogs, small molecule inhibitors of enzymes such as sphingosine kinase, acid ceramidase or ceramide synthase that catalyze ceramide catabolism or its conversion to various molecular species and S1P receptor antagonists. These approaches mainly aim to up-regulate the levels of apoptotic shingolipids while the proliferative ones are down-regulated, or to directly deliver cytotoxic sphingolipids like short-chain ceramide analogs to tumor cells. It is suggested that a combination therapy with conventional cytotoxic approaches while preventing the conversion of ceramide to S1P and consequently increasing the ceramide levels would be more beneficial. This review compiles the current knowledge about sphingolipids, and mainly focuses on novel agents modulating sphingolipid pathways that represent recent therapeutic strategies for the treatment of cancer.
鞘脂是一类在多种细胞过程中具有重要功能的脂质，如分化、增殖、衰老、凋亡和化疗耐药。研究最广泛的生物活性鞘脂包括神经酰胺、二氢神经酰胺 (dhCer)、神经酰胺-1-磷酸 (C1P)、葡萄糖神经酰胺 (GluCer)、鞘氨醇和鞘氨醇-1-磷酸 (S1P)。尽管脂肪酸链的长度会影响其生理作用，但神经酰胺和鞘氨醇已知可诱导细胞凋亡，而 C1P、S1P 和 GluCer 则可诱导细胞增殖，从而导致化疗耐药的发展。先前的研究表明，生物活性鞘脂在肿瘤发生、癌症进展以及药物和辐射耐药性方面具有重要意义。因此，靶向鞘脂代谢的元素似乎对开发新的治疗方法或提高当前治疗策略的有效性很重要。一些方法涉及合成神经酰胺类似物的开发、酶的小分子抑制剂，如鞘氨醇激酶、酸性神经酰胺酶或神经酰胺合酶，这些酶可催化神经酰胺分解代谢或将其转化为各种分子种类以及 S1P 受体拮抗剂。这些方法主要旨在上调促凋亡鞘脂的水平，同时下调促增殖的鞘脂，或者直接将细胞毒性短链神经酰胺类似物等递送到肿瘤细胞中。有人建议，联合使用常规细胞毒性方法，同时防止神经酰胺转化为 S1P，并因此增加神经酰胺水平，可能会更有益。本综述汇集了关于鞘脂的现有知识，主要侧重于调节鞘脂途径的新型药物，这些药物代表了癌症治疗的最新治疗策略。
