对于头颈部鳞状细胞癌(HNSCC)患者，手术和/或基于铂的化疗和放疗仍然是标准治疗方法。尽管这些疗法对部分患者有效，但相当大比例的患者会出现复发或治疗耐药。由于顺铂通过氧化应激介导细胞毒作用，而多胺在氧化还原调节中发挥作用，我们假设将顺铂与多胺转运抑制剂AMXT-1501联合使用，可以增加HNSCC细胞内的氧化应激，促进肿瘤细胞死亡。以顺铂±AMXT-1501处理同基因小鼠HNSCC细胞株来测量细胞增殖。通过在 vitro 化疗细胞株时以顺铂和AMXT-1501的比例1：10进行联合治疗来确定协同作用。将癌细胞转移到小鼠躯体上，测试治疗方法在 vivo 中的疗效。测量了产生的活性氧(ROS)。使用流式细胞术和Annexin V/PI染色法来测量细胞凋亡。采用高效液相色谱(HPLC)来定量细胞系中的多胺。在存在外源性阳离子氨基酸时，测量细胞活力和ROS。顺铂和AMXT-1501的联合治疗能够在 vitro 中对HNSCC细胞株产生协同作用。在 vivo 联合治疗结果显示肿瘤生长抑制效果高于单独治疗。联合治疗增加了ROS的产生并诱导细胞凋亡。HPLC揭示协同机制与细胞内多胺水平无关。补充阳离子氨基酸部分恢复了癌细胞的活力并减少了ROS。AMXT-1501通过多胺非依赖机制增强了顺铂对侵袭性HNSCC细胞株的 in vitro 和 in vivo 细胞毒作用。

Surgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells.Cell proliferation was measured in syngeneic mouse HNSCC cell lines treated with cisplatin ± AMXT-1501. Synergy was determined by administering cisplatin and AMXT-1501 at a ratio of 1:10 to cancer cells in vitro . Cancer cells were transferred onto mouse flanks to test the efficacy of treatments in vivo . Reactive oxygen species (ROS) were measured. Cellular apoptosis was measured with flow cytometry using Annexin V/PI staining. High-performance liquid chromatography (HPLC) was used to quantify polyamines in cell lines. Cell viability and ROS were measured in the presence of exogenous cationic amino acids.The combination of cisplatin and AMXT-1501 synergize in vitro on HNSCC cell lines. In vivo combination treatment resulted in tumor growth inhibition greater than either treatment individually. The combination treatment increased ROS production and induced apoptotic cell death. HPLC revealed the synergistic mechanism was independent of intracellular polyamine levels. Supplementation of cationic amino acids partially rescued cancer cell viability and reduced ROS.AMXT-1501 enhances the cytotoxic effects of cisplatin in vitro and in vivo in aggressive HNSCC cell lines through a polyamine-independent mechanism.