Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, SI-1000 Ljubljana, Slovenia.
Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia.
Mar Drugs. 2018 Oct 3;16(10):367. doi: 10.3390/md16100367.
The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung cancer, we determined its systemic and organ-specific toxicity in mice, evaluated its antitumor activity against adenocarcinoma xenograft models, and examined the mechanisms of APS8 in terms of apoptosis, cytotoxicity, and viability. We also measured Ca influx into cells, and evaluated the effects of APS8 on Ca uptake while siRNA silencing of the gene for α7 nAChRs, . APS8 was not toxic to mice up to 5 mg/kg i.v., and no significant histological changes were observed in mice that survived APS8 treatment. Repetitive intratumoral injections of APS8 (4 mg/kg) significantly delayed growth of A549 cell tumors, and generally prevented regrowth of tumors, but were less effective in reducing growth of HT29 cell tumors. APS8 impaired the viability of A549 cells in a dose-dependent manner and induced apoptosis at micro molar concentrations. Nano molar APS8 caused minor cytotoxic effects, while cell lysis occurred at APS8 >3 µM. Furthermore, Ca uptake was significantly reduced in APS8-treated A549 cells. Observed differences in response to APS8 can be attributed to the number of α7 nAChRs expressed in these cells, with those with more AChRs (i.e., A549 cells) being more sensitive to nAChR antagonists like APS8. We conclude that α7 nAChR antagonists like APS8 have potential to be used as therapeutics for tumors expressing large numbers of α7 nAChRs.
烷基吡啶聚合物 APS8 是一种强效的α7 烟碱型乙酰胆碱受体 (nAChR) 拮抗剂，它选择性地诱导非小细胞肺癌细胞凋亡，而不诱导正常肺成纤维细胞凋亡。为了探索 APS8 对至少某些类型肺癌的潜在治疗价值，我们在小鼠中确定了其全身和器官特异性毒性，评估了其对腺癌异种移植模型的抗肿瘤活性，并研究了 APS8 在凋亡、细胞毒性和活力方面的机制。我们还测量了细胞内的 Ca 流入，并评估了 APS8 对 Ca 摄取的影响，同时用 α7 nAChR 的基因 siRNA 沉默。APS8 在高达 5mg/kg 的静脉内给药时对小鼠没有毒性，并且在接受 APS8 治疗的小鼠中没有观察到明显的组织学变化。重复的肿瘤内注射 APS8（4mg/kg）显著延迟了 A549 细胞肿瘤的生长，并且通常阻止了肿瘤的重新生长，但在减少 HT29 细胞肿瘤的生长方面效果较差。APS8 以剂量依赖性方式损害 A549 细胞的活力，并在微摩尔浓度下诱导凋亡。纳摩尔 APS8 引起轻微的细胞毒性作用，而在 APS8>3µM 时发生细胞溶解。此外，在 APS8 处理的 A549 细胞中，Ca 摄取显著减少。对 APS8 反应的差异可归因于这些细胞中表达的α7 nAChR 的数量，其中表达更多 AChR 的细胞（即 A549 细胞）对 APS8 等 nAChR 拮抗剂更敏感。我们得出结论，像 APS8 这样的α7 nAChR 拮抗剂有可能被用作表达大量α7 nAChR 的肿瘤的治疗药物。
