State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu, China.
Drug Deliv. 2021 Dec;28(1):2480-2494. doi: 10.1080/10717544.2021.2000677.
Cisplatin (DDP) is a first-line chemotherapeutic drug applied for the treatment of oral squamous cell carcinoma (OSCC). The anticancer activity of DDP is tightly linked to its intracellular uptake. It is unwise to increase the DDP intake by increasing the dose or shortening the dosing interval because of the severe systemic toxicity (nephrotoxicity, ototoxicity and neurotoxicity) in DDP application. The main uptake pathways of DDP include passive diffusion and active transporter transport. Therefore, finding additional uptake pathways that can improve the effective intracellular concentration of DDP is critical. Macropinocytosis, an endocytic mechanism for extracellular material absorption, contributes to the intracellular uptake of anticancer drugs. No research has been conducted to determine whether macropinocytosis can augment the intracellular uptake of DDP in OSCC cells or not. Based on that, we proved for the first time that silmitasertib (previously CX-4945) could trigger macropinocytosis, which may increase the intracellular uptake of DDP and enhance apoptosis via and experiments. We hope that our findings will inspire a new approach for the application of DDP in cancer treatment.
顺铂（DDP）是一种用于治疗口腔鳞状细胞癌（OSCC）的一线化疗药物。DDP 的抗癌活性与其细胞内摄取紧密相关。由于 DDP 应用中的严重全身毒性（肾毒性、耳毒性和神经毒性），增加剂量或缩短给药间隔以增加 DDP 摄入是不明智的。DDP 的主要摄取途径包括被动扩散和主动转运体运输。因此，寻找可以提高 DDP 的有效细胞内浓度的其他摄取途径至关重要。巨胞饮作用是细胞外物质吸收的一种胞吞作用机制，有助于抗癌药物的细胞内摄取。目前尚无研究确定巨胞饮作用是否可以增加 OSCC 细胞中 DDP 的细胞内摄取。基于此，我们首次证明 silmitasertib（以前称为 CX-4945）可以触发巨胞饮作用，这可能通过 和 实验增加 DDP 的细胞内摄取并通过 和 促进细胞凋亡。我们希望我们的发现将为 DDP 在癌症治疗中的应用开辟新途径。
