Dclk1 Inhibition Cancels 5-FU-induced Cell-cycle Arrest and Decreases Cell Survival in Colorectal Cancer

Abstract

Background/aim: 5-Fluorouracil (5-FU) is frequently used in colorectal cancer treatment, but with limited success. The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of doublecortin-like kinase 1 (Dclk1), a tumor stem cell marker that regulates pro-survival signaling in colorectal cancer cells, in the human colon cancer cell line, COLO-320.

Materials and methods: The effects of 5-FU treatment plus Dclk1 inhibition on the phosphorylation of checkpoint kinase 1 (Chk1), cell cycle, DNA damage, apoptosis, and cell survival in COLO-320 cells were evaluated.

Results: Combined treatment with 5-FU and a Dclk1 inhibitor, LRRK2-IN-1 (LRRK), decreased 5-FU-induced phosphorylation of Chk1 and canceled 5-FU-induced cell-cycle arrest at the S phase. Combined treatment with 5-FU and LRRK failed to induce poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, but tended to decrease cell survival compared to individual treatment with 5-FU or LRRK.

Conclusion: These results indicate that a combination of 5-FU and LRRK may be an effective, novel approach for colorectal cancer therapy.

Keywords: 5-fluorouracil; Colorectal cancer; LRRK2-IN-1; cell-cycle arrest; checkpoint kinase 1 phosphorylation; cytotoxicity; doublecortin-like kinase 1.