摘要
胃癌是全球最常见的恶性肿瘤之一,也是癌症相关死亡的第三大原因。在本研究中,我们研究了 OSI-027 的潜在活性,OSI-027 是雷帕霉素复合物 1/2 (mTOR1/2) 双重抑制剂的强效和选择性哺乳动物靶标,单独或与奥沙利铂联合用于体外对抗胃癌细胞。进行细胞计数 kit-8 测定和 EdU 染色以检查癌细胞的增殖。流式细胞仪检测细胞周期和细胞凋亡。 Western印迹用于检测胃癌细胞系中mTOR途径和P-gp的元件。 OSI-027 通过将细胞周期阻滞在 G0/G1 期来抑制 MKN-45 和 AGS 细胞的增殖。在分子水平上,OSI-027 同时阻断 mTORC1 和 mTORC2 的激活,并导致磷光体 Akt、phpspho-p70S6k、磷光体 4EBP1、细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 4 (CDK4) 的下调。此外,OSI-027 还下调 P-gp,从而增强奥沙利铂诱导的细胞凋亡并抑制多药耐药性。此外,OSI-027 在体外表现出与奥沙利铂的协同细胞毒作用,而 P-gp siRNA 敲低显着抑制了协同作用。总之,我们的结果表明,应进一步研究 mTORC1/mTORC2 双重抑制剂(例如 OSI-027)作为胃癌潜在有价值的治疗方法。
关键词: 胃癌,OSI-027,奥沙利铂,mTOR,P-gp,多药耐药。
Current Molecular Medicine
Title:OSI-027 Alleviates Oxaliplatin Chemoresistance in Gastric Cancer Cells by Suppressing P-gp Induction
Volume: 21 Issue: 10
关键词: 胃癌,OSI-027,奥沙利铂,mTOR,P-gp,多药耐药。
摘要: Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and P-gp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potentially valuable treatment for gastric cancer.
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Cite this article as:
OSI-027 Alleviates Oxaliplatin Chemoresistance in Gastric Cancer Cells by Suppressing P-gp Induction, Current Molecular Medicine 2021; 21 (10) . https://dx.doi.org/10.2174/1566524020666201120113538
DOI https://dx.doi.org/10.2174/1566524020666201120113538 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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