Drug-induced tumor-specific cytotoxicity in a whole tissue ex vivo model of human pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. PDAC has a dismal prognosis and an inherent resistance to cytostatic drugs. The lack of reliable experimental models is a severe limitation for drug development targeting PDAC. We have employed a whole tissue ex vivo culture model to explore the effect of redox-modulation by sodium selenite on the viability and growth of PDAC. Drug-resistant tumors are more vulnerable to redox-active selenium compounds because of high metabolic activity and redox imbalance. Sodium selenite efficiently and specifically reduced PDAC cell viability (p <0.02) (n=8) and decreased viable de novo tumor cell outgrowth (p<0.05) while preserving non-neoplastic tissues. Major cellular responses (damaged tumor cells > 90%, tumor regression grades III-IV according to Evans) were observed for sodium selenite concentrations between 15-30 µM. Moreover, selenium levels used in this study were significantly below the previously reported maximum tolerated dose for humans. Transcriptome data analysis revealed decreased expression of genes known to drive PDAC growth and metastatic potential (CEMIP, DDR2, PLOD2, P4HA1) while the cell death-inducing genes (ATF3, ACHE) were significantly upregulated (p<0.0001). In conclusion, we report that sodium selenite has an extraordinary efficacy and specificity against drug-resistant pancreatic cancer in an organotypic slice culture model. Our ex vivo organotypic tissue slice culture model can be used to test a variety of drug candidates for swift and reliable drug responses to individual PDAC cases.

Intravenous Infusion of High Dose Selenite in End-Stage Cancer Patients: Analysis of Systemic Exposure to Selenite and Seleno-Metabolites

“…Most cancer cells are sensitive to from moderate to high concentrations in the span of 5-15 µM [3,4]. In fact, 15-30 µM proved to be exceptionally efficient in an ex vivo tissue culture of human pancreatic ductal adenocarcinoma with a marked specificity to tumor cell cytotoxicity and had a limited or no effect on ambient tissues [20]. The exposure time is also important and, in laboratory experiments, the maximum effect is usually observed after 48 h of exposure-a factor that might be one explanation for the lack of tumor response in the SECAR trial.…”

Trace elements in pancreatic cancer

“… 45 Sodium selenite decreases the expression of genes that promote PCA metastasis (CEMIP, DDR2, PLOD2, and P4HA1) and increases the expression of the ATF3 gene, which promotes ferroptosis in PCACs, thereby specifically reducing the activity of PCACs and inhibiting tumor growth. 46 NF‐κB is involved in the development of PCA and inhibits the apoptosis of PCACs. 47 A novel selenoaspirinyl compound that can induce caspase‐mediated apoptosis and G1 cell cycle arrest inhibits NF‐κB signaling to inhibit PCACs proliferation, and it can enhance the cytotoxicity of gemcitabine to PCA.…”

Research on the biological mechanism and potential application of CEMIP

“…Transcription factors also play an essential role in regulating CEMIP (22). In a study of gastric cancer (GC), activating transcription factor 3 (ATF3) inhibited the activity of CEMIP promoter (23).…”