Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
World J Gastroenterol. 2024 Feb 21;30(7):714-727. doi: 10.3748/wjg.v30.i7.714.
Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψ), facilitate tumor cell uptake of Δψ-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect.
To determine whether erlotinib can elevate Δψ and increase tumor cell uptake of Δψ-sensitive agents, subsequently triggering tumor cell death.
Δψ-sensitive fluorescent dye was used to determine how erlotinib affects Δψ in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψ-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.
Erlotinib elevated Δψ in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψ-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.
Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.
胰腺癌是癌症相关死亡的主要原因。表皮生长因子受体（EGFR）的活性增加通常在胰腺癌中观察到，小分子 EGFR 抑制剂厄洛替尼已被食品和药物管理局批准用于胰腺癌治疗。然而，厄洛替尼单独使用无效，应与其他药物联合使用以提高治疗效果。我们之前表明，某些受体酪氨酸激酶抑制剂可以增加线粒体膜电位（Δψ），促进肿瘤细胞摄取 Δψ 敏感剂，破坏线粒体平衡，随后触发肿瘤细胞死亡。尚未对厄洛替尼进行此效果的测试。
确定厄洛替尼是否可以升高 Δψ 并增加肿瘤细胞摄取 Δψ 敏感剂，随后触发肿瘤细胞死亡。
使用 Δψ 敏感荧光染料来确定厄洛替尼如何影响胰腺腺癌（PDAC）细胞系中的 Δψ。用厄洛替尼和线粒体靶向泛醌（MitoQ），一种 Δψ 敏感的 MitoQ 依次处理细胞后，测量常规和源自患者的原发性 PDAC 细胞系在 2D 和 3D 培养中的活力。然后使用 SynergyFinder 2.0 分析厄洛替尼和 MitoQ 之间的协同作用。使用携带 PDAC 细胞系异种移植物的免疫缺陷裸鼠来确定两药组合的临床前疗效。
厄洛替尼升高了 PDAC 细胞中的 Δψ，促进了肿瘤细胞摄取和 Δψ 敏感剂的线粒体富集。如果使用高剂量，MitoQ 会在线粒体培养的 PDAC 细胞中引发 caspase 依赖性细胞凋亡，而厄洛替尼预处理则增强了低剂量的 MitoQ。SynergyFinder 表明这些药物协同诱导肿瘤细胞致死。与数据一致，厄洛替尼和 MitoQ 联合治疗比单独使用每种药物更有效地抑制了小鼠中的人 PDAC 细胞系异种移植物。
我们的研究结果表明，厄洛替尼和 MitoQ 的联合使用有可能有效地抑制胰腺肿瘤细胞的活力。
