Extracellular Vesicles Inhibit the Response of Pancreatic Ductal Adenocarcinoma Cells to Gemcitabine and TRAIL Treatment

Abstract

Pancreatic ductal adenocarcinoma remains an aggressive cancer with a low 5-year survival rate. Although gemcitabine has been a standard treatment for advanced pancreatic cancer, patients often develop resistance to this therapeutic. We have previously shown that treating pancreatic cancer cells in vitro with a combination of gemcitabine and the cytokine TRAIL significantly reduced both cell viability and survival. The data presented here demonstrate that this response to treatment is inhibited when cells are incubated with a conditioned medium derived from untreated cells. We show that this inhibition is specifically mediated by extracellular vesicles present in the conditioned medium, as seen by a significant decrease in apoptosis. Additionally, we further demonstrate that this effect can be reversed in the presence of GW4869, an inhibitor of exosome biogenesis and release. These results show that pancreatic cancer cell-derived extracellular vesicles can confer resistance to treatment with gemcitabine and TRAIL. The implications of these findings suggest that removal of EVs during treatment can improve the response of cells to gemcitabine and TRAIL treatment in vitro.

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system

“…Interestingly, in our validation, the treatment of HNSCC cells with this known inhibitor of EV biosynthesis did not significantly affect cell viability or cell morphology, but it enhanced the antitumor effect of CDDP, which in turn led to a clear decrease in ATP7B expression (Figures 4 and 5). Rimmer et al reported that the antitumor effect of gemcitabine on pancreatic cancer cells was enhanced under a GW4869 combination 60 . Others have reported that the combination of GW4869 and doxorubicin against acute myeloid leukemia similarly enhanced sensitivity to chemotherapy 51 .…”

“…Rimmer et al reported that the antitumor effect of gemcitabine on pancreatic cancer cells was enhanced under a GW4869 combination. 60 Others have reported that the combination of GW4869 and doxorubicin against acute myeloid leukemia similarly enhanced sensitivity to chemotherapy. 51 Abad et al revealed a new mechanism of acquired chemotherapy resistance in triple negative breast cancer (TNBC) cells, in which EVs transport mitochondria to susceptible cancer cells and enhance their resistance to chemotherapy.…”

Development of handheld induction heaters for magnetic fluid hyperthermia applications and in-vitro evaluation on ovarian and prostate cancer cell lines

“…Then, the buffer was discarded to fill the plate with 2.0 ml of fresh media. The dish was then moved to the incubator for 24 h or 48 h before detaching and suspending the cells to count them manually and assess cell viability with the Trypan Blue exclusion assay (see subsection C of the Supplementary Information) [23,58,59]. See figure 4 for a graphical depiction of the plate management.…”