Levi Lirit, Hikri Elad, Popovtzer Aron, Dayan Avraham, Levi Amir, Bachar Gideon, Mizrachi Aviram, Shoffel-Havakuk Hagit
Department of Otorhinolaryngology-Head and Neck Surgery, Rabin Medical Center, Petach Tikva 49100, Israel.
Translational Research in Head and Neck Cancer, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Tel Aviv 6997801, Israel.
J Clin Med. 2023 Feb 6;12(4):1277. doi: 10.3390/jcm12041277.
Recent studies suggest that opioids have a role in the progression of HNSCC mediated by mu opioid receptors (MOR), however, the effects of their activation or blockage remains unclear. Expression of MOR-1 was explored in seven HNSCC cell lines using Western blotting (WB). XTT cell proliferation and cell migration assays were performed on four selected cell lines (Cal-33, FaDu, HSC-2, and HSC-3), treated with opiate receptor agonist (morphine), antagonist (naloxone), alone and combined with cisplatin. All four selected cell lines display an increased cell proliferation and upregulation of MOR-1 when exposed to morphine. Furthermore, morphine promotes cell migration, while naloxone inhibits it. The effects on cell signaling pathways were analyzed using WB, demonstrating morphine activation of AKT and S6, key proteins in the PI3K/AKT/mTOR axis. A significant synergistic cytotoxic effect between cisplatin and naloxone in all cell lines is observed. In vivo studies of nude mice harboring HSC3 tumor treated with naloxone demonstrate a decrease in tumor volume. The synergistic cytotoxic effect between cisplatin and naloxone is observed in the in vivo studies as well. Our findings suggest that opioids may increase HNSCC cell proliferation via the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, MOR blockage may chemo-sensitize HNSCC to cisplatin.
最近的研究表明，阿片类药物在由μ阿片受体（MOR）介导的头颈部鳞状细胞癌（HNSCC）进展中起作用，然而，其激活或阻断的效果仍不清楚。使用蛋白质印迹法（WB）在七种HNSCC细胞系中探究了MOR-1的表达。对四种选定的细胞系（Cal-33、FaDu、HSC-2和HSC-3）进行XTT细胞增殖和细胞迁移试验，这些细胞系分别用阿片受体激动剂（吗啡）、拮抗剂（纳洛酮）单独处理以及与顺铂联合处理。所有四种选定的细胞系在暴露于吗啡时均显示细胞增殖增加和MOR-1上调。此外，吗啡促进细胞迁移，而纳洛酮抑制细胞迁移。使用WB分析对细胞信号通路的影响，结果表明吗啡激活了PI3K/AKT/mTOR轴中的关键蛋白AKT和S6。在所有细胞系中均观察到顺铂和纳洛酮之间有显著的协同细胞毒性作用。对携带HSC3肿瘤的裸鼠进行纳洛酮体内研究，结果显示肿瘤体积减小。在体内研究中也观察到顺铂和纳洛酮之间的协同细胞毒性作用。我们的研究结果表明，阿片类药物可能通过激活PI3K/Akt/mTOR信号通路增加HNSCC细胞增殖。此外，MOR阻断可能使HNSCC对顺铂产生化疗敏感性。
