School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, P.R. China.
Oncol Rep. 2021 Mar;45(3):1306-1314. doi: 10.3892/or.2021.7950. Epub 2021 Jan 22.
Non‑small cell lung cancer (NSCLC) remains an intractable disease, which is primarily due to tumor metastasis and the acquisition of resistance to chemotherapy. Therefore, there is an urgent need for novel therapeutics to overcome these obstacles. It was recently demonstrated that upregulated expression of monoamine oxidase A (MAOA) contributes to the progression of NSCLC. G10, a tumor‑targeting representative conjugate of heptamethine carbocyanine dye and an inhibitor of MAOA, was shown to exert potent cytotoxic effects, comparable to those of doxorubicin, against prostate cancer cell lines, as well as moderate MAOA inhibitory activity. The research described herein aimed to extend our previous study on the antitumor function of G10 in NSCLC in vitro and in vivo, and to elucidate the mechanisms through which G10 exerts its antineoplastic effects. G10 markedly inhibited the proliferation of paclitaxel‑resistant NSCLC cells (H460/PTX) and reduced tumor cell migration and invasion. Gene expression profiling of paclitaxel‑resistant NSCLC cells following treatment with G10 demonstrated that the expression of genes associated with the extracellular matrix was significantly affected, particularly the metastasis‑related genes matrix metallopeptidase (MMP)2, MMP14 and COL6A, which exhibited notably reduced expression. Additionally, the results also demonstrated that MAOA‑related pathways, including AKT and hypoxia‑inducible factor‑1α, were also inhibited by G10 treatment and, subsequently, the downstream molecules of these pathways, such as p21, MMP2 and vascular endothelial growth factor, were also downregulated, highlighting a possible mechanism through which G10 suppresses tumor cell migration, invasion and proliferation. Importantly, in mouse NSCLC xenografts, combined treatment with G10 and paclitaxel resulted in pronounced inhibition of tumor growth. Taken together, the results of the present study highlight the potential of G10 as a novel therapeutic targeting MAOA in paclitaxel‑resistant NSCLC.
非小细胞肺癌（NSCLC）仍然是一种难以治疗的疾病，主要是由于肿瘤转移和对化疗的耐药性。因此，迫切需要新的治疗方法来克服这些障碍。最近的研究表明，单胺氧化酶 A（MAOA）的上调表达促进了 NSCLC 的进展。G10 是一种七甲川花菁染料的肿瘤靶向代表缀合物，也是 MAOA 的抑制剂，它对前列腺癌细胞系表现出强大的细胞毒性作用，与多柔比星相当，并且具有适度的 MAOA 抑制活性。本研究旨在扩展我们之前关于 G10 在 NSCLC 中的抗肿瘤功能的研究，包括体内和体外研究，并阐明 G10 发挥抗肿瘤作用的机制。G10 显著抑制紫杉醇耐药 NSCLC 细胞（H460/PTX）的增殖，并减少肿瘤细胞迁移和侵袭。用 G10 处理紫杉醇耐药 NSCLC 细胞后的基因表达谱分析表明，与细胞外基质相关的基因表达显著受到影响，特别是与转移相关的基因基质金属蛋白酶（MMP）2、MMP14 和 COL6A，其表达明显降低。此外，结果还表明，MAOA 相关途径，包括 AKT 和缺氧诱导因子-1α，也被 G10 处理抑制，随后这些途径的下游分子，如 p21、MMP2 和血管内皮生长因子，也下调，突出了 G10 抑制肿瘤细胞迁移、侵袭和增殖的可能机制。重要的是，在小鼠 NSCLC 异种移植模型中，G10 与紫杉醇联合治疗显著抑制肿瘤生长。综上所述，本研究结果强调了 G10 作为一种新型治疗剂靶向 MAOA 在紫杉醇耐药 NSCLC 中的潜力。
