Topically applicated curcumin/gelatin-blended nanofibrous mat inhibits pancreatic adenocarcinoma by increasing ROS production and endoplasmic reticulum stress mediated apoptosis

Abstract

Background Pancreatic adenocarcinoma (PDAC) is one of the most fatal malignancies. Surgical resection supplemented by chemotherapy remains the major therapeutic regimen, but with unavoidable resistance and systemic toxic reaction. Curcumin is a known safe natural compound that can effectively eliminate pancreatic adenocarcinoma cells in vitro, making it a promising candidate for substitution in subsequent chemotherapy. However, due to its extremely low bioavailability caused by its insolubility and circular elimination, curcumin had an unexpectedly modest therapeutic effect in clinical trials. Results Here, we electrospun curcumin/gelatin-blended nanofibrous mat to largely improve curcumin’s bioavailability by local controlled-release. With characterization by scanning electron microscopy, fluorescence microscopy, Fourier transform infrared spectroscopy, X-ray diffraction and high-performance liquid chromatography, it was revealed that curcumin was uniformly dispersed in the fiber of the mats with nanoscopic dimensions and could be continuously released into the surrounding medium for days. The cancer inhibitory effects of nano-curcumin and underlying mechanisms were further explored by assays using pancreatic adenocarcinoma cell and experiments using xenograft model. The results showed the released nano-curcumin could effectively inhibit pancreatic adenocarcinoma cell proliferation not only in vitro, but more importantly in vivo. This cytotoxic effect of nano-curcumin against pancreatic adenocarcinoma was achieved through provoking the production of intracellular reactive oxygen species and activating endoplasmic reticulum stress, which leads to enhanced cell apoptosis via decreased phosphorylation of signal transducer and activator of transcription 3. Conclusions Clinically, curcumin/gelatin-blended nanofibrous mat could be a promising, secure, efficient and affordable substitutional agent for the elimination of residual cancer cells after tumor resection. Moreover, our strategy to obtain curcumin released from nanofibrous mat may provide a universally applicable approach for the study of the therapeutic effects and molecular mechanisms of other potential medicines with low bioavailability.

Alizarin, a nature compound, inhibits the growth of pancreatic cancer cells by abrogating NF-κB activation

“…Among them, paclitaxel, curcumin and alizarin showed better inhibitory effects than the others. There have already been many studies about paclitaxel and curcumin in the pancreatic cancer field, and these agents have shown potent tumor-inhibitory capability 13 , 14 , consistent with our work. However, to date, no study has uncovered a suppressive effect of alizarin on pancreatic cancer cells.…”

“…1 ). However, there have already been many studies on paclitaxel and curcumin 13 , 14 , which have reported that these agents have potent inhibitory effects on pancreatic tumor cells, and our results are consistent with these existing studies. Nevertheless, there has not been any proof of the antitumor activity of alizarin in pancreatic cancer.…”

Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells

“…A high level of ROS can also increase the susceptibility of tumor cells to oxidative stress-induced cell death, which could be a potential strategy for cancer therapy [44]. ROS has been found to induce endoplasmic reticulum stress and promote apoptosis of PC cells [45]. Previous studies have demonstrated that oxaliplatin induces intracellular ROS production and accumulation, which contributes to its anti-cancer activity [28].…”

Mechanisms Underlying Curcumin-Induced Neuroprotection in Cerebral Ischemia

“… Xu et al (2018 ) showed that a combination of curcumin and vagus nerve stimulation restored behavioral deficits by inhibiting apoptosis after cerebral ischemia, with the involvement of the Akt/ERK2 pathway. Notably, curcumin inhibits cellular damage and apoptosis by diminishing the endoplasmic reticulum stress (ERS) ( Cheng et al, 2020 ; Keshk et al, 2020 ; Zhou et al, 2022 ). Chhunchha et al (2013 ) reported that curcumin abated hypoxia-induced ERS-mediated cell death in mouse hippocampal cells by enhancing peroxiredoxin 6 (Prdx6) expressions and inhibiting NF-κB activation.…”