Torrens-Mas Margalida, Collado-Solé Alejandro, Sola-Leyva Alberto, Carrasco-Jiménez María Paz, Oliver Jordi, Pons Daniel Gabriel, Roca Pilar, Sastre-Serra Jorge
Grupo Multidisciplinar de Oncología Traslacional, Research Institute of Health Sciences (IUNICS), University of Balearic Islands, 07122 Palma de Mallorca, Spain.
Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias, University of Granada, Av. Fuentenueva s/n, 18001 Granada, Spain.
Biology (Basel). 2023 Nov 22;12(12):1457. doi: 10.3390/biology12121457.
Alkylphospholipids (APLs) have been studied as anticancer drugs that interfere with biological membranes without targeting DNA. Although their mechanism of action is not fully elucidated yet, it is known that they disrupt the intracellular trafficking of cholesterol and its metabolism. Here, we analyzed whether APLs could also interfere with mitochondrial function. For this purpose, we used HT29 colorectal cancer cells, derived from a primary tumor, and SW620 colorectal cancer cells, derived from a metastasis site. After treatment with the APLs miltefosine and perifosine, we analyzed various mitochondrial parameters, including mitochondrial mass, cardiolipin content, mitochondrial membrane potential, HO production, the levels of oxidative phosphorylation (OXPHOS) complexes, metabolic enzymes activity, the oxygen consumption rate, and the levels of apoptosis and autophagy markers. APLs, especially perifosine, increased mitochondrial mass while OXPHOS complexes levels were decreased without affecting the total oxygen consumption rate. Additionally, we observed an increase in pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase (IDH) levels and a decrease in lactate dehydrogenase (LDH) activity, suggesting a metabolic rewiring induced by perifosine. These alterations led to higher mitochondrial membrane potential, which was potentiated by decreased uncoupling protein 2 (UCP2) levels and increased reactive oxygen species (ROS) production. Consequently, perifosine induced an imbalance in mitochondrial function, resulting in higher ROS production that ultimately impacted cellular viability.
烷基磷脂（APLs）已被作为抗癌药物进行研究，这类药物可干扰生物膜而不靶向DNA。尽管其作用机制尚未完全阐明，但已知它们会破坏胆固醇的细胞内运输及其代谢。在此，我们分析了APLs是否也会干扰线粒体功能。为此，我们使用了源自原发性肿瘤的HT29结肠癌细胞和源自转移部位的SW620结肠癌细胞。在用APLs米替福新和哌立福新处理后，我们分析了各种线粒体参数，包括线粒体质量、心磷脂含量、线粒体膜电位、HO产生、氧化磷酸化（OXPHOS）复合物水平、代谢酶活性、氧消耗率以及凋亡和自噬标志物的水平。APLs，尤其是哌立福新，增加了线粒体质量，而OXPHOS复合物水平降低，同时不影响总氧消耗率。此外，我们观察到丙酮酸脱氢酶（PDH）和异柠檬酸脱氢酶（IDH）水平升高，乳酸脱氢酶（LDH）活性降低，这表明哌立福新诱导了代谢重编程。这些改变导致线粒体膜电位升高，这因解偶联蛋白2（UCP2）水平降低和活性氧（ROS）产生增加而增强。因此，哌立福新诱导线粒体功能失衡，导致ROS产生增加，最终影响细胞活力。
