Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with poor prognosis and limited therapeutic options. Alternating electrical fields with low intensity called “Tumor Treating Fields” (TTFields) are a new, non-invasive approach with almost no side effects and phase 3 trials are ongoing in advanced PDAC. We evaluated TTFields in combination with mild hyperthermia. Three established human PDAC cell lines and an immortalized pancreatic duct cell line were treated with TTFields and hyperthermia at 38.5°C, followed by microscopy, assays for MTT, migration, colony and sphere formation, RT-qPCR, FACS, Western blot, microarray and bioinformatics, and in silico analysis using the online databases GSEA, KEGG, Cytoscape-String, and Kaplan-Meier Plotter. Whereas TTFields and hyperthermia alone had weak effects, their combination strongly inhibited the viability of malignant, but not those of nonmalignant cells. Progression features and the cell cycle were impaired, and autophagy was induced. The identified target genes were key players in autophagy, the cell cycle and DNA repair. The expression profiles of part of these target genes were significantly involved in the survival of PDAC patients. In conclusion, the combination of TTFields with mild hyperthermia results in greater efficacy without increased toxicity and could be easily clinically approved as supporting therapy.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) has an exceptionally poor prognosis, high therapy resistance, and high rates of early metastasis [1]
Our present study investigated whether a combination of mild hyperthermia of 38.5°C and TTFields of less than 1 V/cm would be more effective than each single treatment alone
Whereas the MTT signal of cells cultured at 37°C in the presence or absence of TTFields continuously increased, it was even higher when the cells were cultured at 38.5°C (Figure 1B)
Summary
Pancreatic ductal adenocarcinoma (PDAC) has an exceptionally poor prognosis, high therapy resistance, and high rates of early metastasis [1]. TTFields inhibit tumor cell division [7] by impairing the polymerization of microtubules and septin filaments during mitosis [7,8,9] and extending the duration of mitosis by the formation of defective mitosis structures [3, 7]. This leads to aneuploidy and genomic instability, termed mitotic catastrophe, followed by cell death and senescence [7, 10]
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