Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, The East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA.
Int J Mol Sci. 2024 Sep 11;25(18):9825. doi: 10.3390/ijms25189825.
The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a "ceramide neutralizer", an unwelcome event, highlighting yet another facet of P-gp's versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp "neutralizes" ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer.
肿瘤抑制性鞘脂神经酰胺被认为是许多类型化疗药物（包括蒽环类、长春花生物碱、鬼臼毒素依托泊苷、紫杉烷类和铂类药物奥沙利铂）细胞毒性作用机制的关键参与者。这些药物可以激活神经酰胺的从头合成或通过鞘磷脂酶刺激神经酰胺的产生，从而限制癌细胞的存活。相反，功能失调的鞘脂代谢是癌症存活和治疗耐药性的一个突出因素，削弱了神经酰胺协调的细胞死亡途径（尤其是细胞凋亡）的抗癌特性。尽管 P 糖蛋白（P-gp）因其在化疗耐药性中的作用而闻名，但在这里，我们提出了替代解释，并讨论了这种多药转运蛋白作为“神经酰胺中和剂”的能力，这是一种不受欢迎的事件，突出了 P-gp 在耐药性方面的多功能性的另一个方面。我们介绍了鞘脂代谢及其在癌症中的功能失调调节，总结了导致化疗耐药性的因素，解释了 P-gp 如何通过加速神经酰胺的糖基化来“中和”神经酰胺，并考虑了 P-gp-神经酰胺连接在癌症治疗中的治疗应用。
