Zhakupova Assem, Zeinolla Adelina, Kokabi Kamilya, Sergazy Shynggys, Aljofan Mohamad
Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan.
Drug Discovery and Development Laboratory, National Laboratory Astana, Astana 010000, Kazakhstan.
Int J Mol Sci. 2025 Apr 15;26(8):3716. doi: 10.3390/ijms26083716.
A significant challenge in cancer treatment is the rising problem of drug resistance that reduces the effectiveness of therapeutic strategies. Current knowledge shows that multiple mechanisms play a role in cancer drug resistance. Another mechanism that has gained attention is the alteration in sphingolipid trafficking and the dysregulation of its metabolism, which was reported to cause cancer-associated drug resistance. Sphingolipids are lipids containing sphingosine and have multiple roles, ranging from lipid raft formation, apoptosis, and cell signaling to immune cell trafficking. Recent studies show that in developing cancer cells, altered or dysregulated sphingolipids are associated with drug efflux and promote the survival of cancer cells by bypassing apoptosis. Upregulated levels of the glucosylceramide synthase (GCS), an enzyme that functions in sphingolipid metabolism, lead to the upregulated ABCB1 gene that induces drug efflux from the cancer cells. These bypass mechanisms make drugs that induce apoptosis in tumor cells ineffective. By highlighting the current findings, this review aims to provide a mechanism of drug resistance caused by the dysregulation of glucosylceramide synthase, sphingosine kinase, and acid ceramidase enzymes as possible therapeutic targets to enhance the effectiveness of the currently used chemotherapeutic agents.
癌症治疗中的一个重大挑战是耐药性问题日益严重，这降低了治疗策略的有效性。目前的知识表明，多种机制在癌症耐药性中起作用。另一个受到关注的机制是鞘脂转运的改变及其代谢失调，据报道这会导致癌症相关的耐药性。鞘脂是含有鞘氨醇的脂质，具有多种作用，从脂筏形成、细胞凋亡和细胞信号传导到免疫细胞转运。最近的研究表明，在癌细胞的发展过程中，鞘脂的改变或失调与药物外排有关，并通过绕过细胞凋亡促进癌细胞的存活。葡萄糖神经酰胺合酶（GCS）水平上调，这是一种在鞘脂代谢中起作用的酶，会导致ABCB1基因上调，从而诱导癌细胞排出药物。这些绕过机制使诱导肿瘤细胞凋亡的药物无效。通过强调当前的研究结果，本综述旨在提供一种由葡萄糖神经酰胺合酶、鞘氨醇激酶和酸性神经酰胺酶失调引起的耐药机制，作为可能的治疗靶点，以提高目前使用的化疗药物的有效性。
