Development of new therapy for colorectal cancer focusing on Dclk1 -Combined treatment with 5FU and Dclk1 inhibitor-

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16363
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Yamaguchi University
• Principal Investigator: TAKEMOTO Yoshihiro 山口大学, 医学部附属病院, 助教 (50622213)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: Dclk1 / 大腸癌 / 5-FU / Chk1

Outline of Final Research Achievements

Background/aim: The aim of the present study was to explore the cytotoxic effects of 5-FU, in combination with inhibition of 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 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, 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.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

Dclk1は大腸癌の癌幹細胞マーカーの候補として注目されるようになり、その他の癌種でも研究が進められている。現在は癌幹細胞マーカーだけではなく、発癌や転移 に関しても重要な役割を果たしている。Dclk1阻害薬もLRRK-IN-1やXMD92など様々な薬剤が存在し、それらを用いた抗腫瘍効果も動物実験レベルで報告されている。臨床では、大腸癌、膵癌、乳癌などの予後不良因子になり得るという報告があるが、治療標的としての研究はまだ進んでいない。本研究は大腸癌に対する化学療法の中心に位置する5-FUの効果を高めるため、Dclk1阻害薬を併用する研究であり、今後の大腸癌治療の進歩に貢献できると思われる。