Background Emerging evidence suggests that highly therapy resistant tumor-initiating cells (TICs) play a central role in the pathogenesis of pancreatic cancer. TRAIL is taken into account as a novel anticancer agent, however, recent studies have shown that many pancreatic cancer cells are resistant to apoptosis induction by TRAIL due to TRAIL-activated NF-κB signaling. Several chemopreventive agents are able to inhibit NF-κB and favourable results have been obtained e.g. for broccoli compound sulforaphane in preventing metastasis in clinical studies.
Aims We aimed to identify TICs in pancreatic carcinoma for analysis of resistance mechanisms and for definition of sensitizing agents.
Methods TICs were defined by expression patterns of a CD44+/CD24-, CD44+/CD24+ or CD44+/CD133+ phenotype and correlation to growth in immunodeficient mice, differentiation grade, clonogenic growth, sphere formation, ALDH activity, and therapy resistance.
Results Mechanistically, we observed specific binding of transcriptionally active cRel-containing NF-κB complexes in TICs. Sulforaphane prevented NF-κB binding, downregulated apoptosis inhibitors and induced apoptosis along with prevention of clonogenicity. Gemcitabine, the chemopreventive agents resveratrol and wogonin, or the death ligand TRAIL were less effective. In a xenograft model, sulforaphane strongly blocked tumor growth and angiogenesis while combination with TRAIL had an additive effect without obvious cytotoxicity on normal cells. Freshly isolated patient tumor cells expressing markers for TICs could be sensitized by sulforaphane for TRAIL-induced cytotoxity.
Conclusion Our data provide new insights into resistance mechanisms of TICs and suggest the combination of sulforaphane with TRAIL as a promising strategy for targeting of pancreatic TICs.