Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer.

BACKGROUND Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-kappa B) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-kappa B pathway. AIM To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-kappa B pathway and reducing the proliferation of colon cancer cells. METHODS Western blot analysis was performed to detect the persistent activation of the NF-kappa B pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-kappa B pathway by blocking the NF-kappa B-regulated IL-1 alpha feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth. RESULTS IL-1 receptor antagonist could decrease the expression of IL-1 alpha and IL-1 beta and downregulate the activity of the NF-kappa B pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-kappa B and MEK pathways resulted in limited proliferation in the SW620 cell line. CONCLUSION Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.