Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.

Effects of Nonsteroidal Anti-inflammatory Drugs on the Self-renewal Capacity of Blast Progenitors in Hematological Malignancies

“…Aspirin has been shown to inhibit colony formation, SR capacity by spheroid-formation assay and tumor growth in a nude mouse xenograft model in breast and pancreatic cancer (25,26). Our present long-term suspension culture, however, enables us to express the SR capacity of blast progenitors as rSLP, compare each rSLP for different agents alone and in combination, and uncover the growth-regulatory mechanisms by adding stimulators or inhibitors to the culture.…”

Chemoresistance in pancreatic cancer: Emerging concepts

“…Hypoxia also results in the accumulation of lactate dehydrogenase-A, which assists in the maintenance of the hypoxic phenotype and increasing chemoresistance (11). Novel molecular targets and molecules that have been identified include: Protein tyrosine kinase-6 (12); vitamin D receptor (VDR) (13); mucin-1 (MUC1) (14); ormeloxifene that targets the sonic hedgehog pathway (15); sodium metaarsenite (KML001) that targets the epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP) 2 (16); the quinazolinedione-based redox modulator QD232 that targets proto-oncogene tyrosine-protein kinase/focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 phosphorylation (17); aspirin, which was revealed to reduce tumor growth and sensitize cells to gemcitabine (18); the curaxin CBL0137, which targets NF-κB and ribonucleotide reductase (19) and sepantronium bromide (YM155) (20)(21)(22), which inhibits the action of inhibitor of apoptosis protein family members (20), as summarized in Table I.…”

Prospected epigenetic moderators from natural sources and drug of class NSAIDS as effective treatment options to Prostate cancer

“…In recent studies ,aspirin beside having anti-inflammatory, anti-pyretic effects via irreversible inactivation of both cycloxygenase(COX) 1 and 2 enzyme in multiple observational studies and controlled randomized trial has also shown promise to be effective as chemopreventive agent like in cancer of prostate, breast, pancreatic and colon either in its original or as modified form [116][117][118][119][120][121].…”