Curcumin Modulates Pancreatic Adenocarcinoma Cell-Derived Exosomal Function

Abstract

Pancreatic cancer has the highest mortality rates of all cancer types. One potential explanation for the aggressiveness of this disease is that cancer cells have been found to communicate with one another using membrane-bound vesicles known as exosomes. These exosomes carry pro-survival molecules and increase the proliferation, survival, and metastatic potential of recipient cells, suggesting that tumor-derived exosomes are powerful drivers of tumor progression. Thus, to successfully address and eradicate pancreatic cancer, it is imperative to develop therapeutic strategies that neutralize cancer cells and exosomes simultaneously. Curcumin, a turmeric root derivative, has been shown to have potent anti-cancer and anti-inflammatory effects in vitro and in vivo. Recent studies have suggested that exosomal curcumin exerts anti-inflammatory properties on recipient cells. However, curcumin’s effects on exosomal pro-tumor function have yet to be determined. We hypothesize that curcumin will alter the pro-survival role of exosomes from pancreatic cancer cells toward a pro-death role, resulting in reduced cell viability of recipient pancreatic cancer cells. The main objective of this study was to determine the functional alterations of exosomes released by pancreatic cancer cells exposed to curcumin compared to exosomes from untreated pancreatic cancer cells. We demonstrate, using an in vitro cell culture model involving pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2, that curcumin is incorporated into exosomes isolated from curcumin-treated pancreatic cancer cells as observed by spectral studies and fluorescence microscopy. Furthermore, curcumin is delivered to recipient pancreatic cancer cells via exosomes, promoting cytotoxicity as demonstrated by Hoffman modulation contrast microscopy as well as AlamarBlue and Trypan blue exclusion assays. Collectively, these data suggest that the efficacy of curcumin may be enhanced in pancreatic cancer cells through exosomal facilitation.

MicroRNA: A novel target of curcumin in cancer therapy

“…Hence, exosomes containing curcumin could be employed as a new option for the treatment of pancreatic cancer (Osterman et al, 2015).…”

“…This finding may indicate that exosomes containing curcumin could improve efficacy of curcumin against pancreatic cancer cells. Hence, exosomes containing curcumin could be employed as a new option for the treatment of pancreatic cancer (Osterman et al, ).…”

Therapeutic use of curcumin‐encapsulated and curcumin‐primed exosomes

“…The efficacy of curcumin-containing exosomes in vivo was also tested using H1299 cells injected into nude mice, followed by either curcumin (300 mg/kg) or exosome daily for 24 days; the curcumintreated mice showed significantly higher TCF21 expression than those treated with vehicle (Wu et al, 2016). (Osterman et al, 2015). Collectively, these data suggest that the efficacy of curcumin as an anticancer and anti-inflammatory agent may be promoted in pancreatic cancer cells through exosomes.…”

Exosomes: Navigating a New Route in Pancreatic Cancer

“…The use of exosomes as drug delivery vehicles has gained considerable interest due to their excellent biodistribution and biocompatibility [81], which should enhance the stability and specificity, and reduce the side effects and immunogenic response, of therapeutic agents. Indeed, Osterman et al showed that exosome-bound curcumin is readily taken up by cultured PDAC cells and is effective in inducing cytotoxicity [82]. Moreover, Pascucci et al demonstrated that mesenchymal stromal cell-derived exosomes can effectively deliver active drugs, such as paclitaxel, to inhibit tumor growth [83].…”