P022 Parthenolide enhances the efficacy of anti-tumour effect of balsalazide in human colon cancer cells and colitis-associated colorectal cancer by blockade of NF-kB activation
G. S. Seo1, S.-L. Kim2, S. W. Kim*2
1Wonkwang university college of medicine, Internal medicine, Iksan, South Korea, 2Chonbuk national university hospital, Internal medicine, Jeonju, South Korea
Balsalazide is a colon-specific prodrug of 5-aminosalicylate (5-ASA) which has been associated with a reduced risk of colon cancer in patients with ulcerative colitis in recent studies. Parthenolide (PT), strong NF-☐B inhibitor has been demonstrated as a promising anticancer agent that promotes apoptosis of cancer cells. In the present study, we investigated the antitumour effect of balsalazide combined with PT by inhibition of nuclear factor-☐B (NF-☐B) activation on human colorectal cancer (CRC).
We evaluated cell viability and cell cycle modifications induced by PT and balsalazide on HCT116 cells. The effects of basalazide combined with PT were evaluated using AOM/DSS-induced CAC in mice clinically and histologically, as assessed by histological injury scores, and suppresses metabolic activity evaluated by 18F-FDG PET/computed tomography (CT) scan and Western blot.
The results demonstrated that combination of balsalazide and PT markedly suppressed proliferation, nuclear translocation of NF-κB, IκB-☐phosphorylation, NF-☐B DNA binding, and expression of NF-kB target proteins. Apoptosis under NF-☐B signalling was confirmed by detecting expression of caspases, p53 and PARP. Moreover, administration of PT and balsalazide to colitis-associated colon cancer (CAC) murine model showed significant recovery of body weight and histological severity. Administration of PT and balsalazide to CAC models were also suppressed carcinogenesis by detecting uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) using micro PET/CT scans. These results demonstrate that PT potentiates the efficacy of balsalazide by synergistic NF-☐B inhibition, and combination of dual agents prevents colon carcinogenesis from chronic inflammation.
This is the first evidence that combination of balsalazide and PT could be a new regimen for colorectal cancer treatment.