Original scientific paper

https://doi.org/10.2478/acph-2023-0025

A novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative inhibits cell proliferation by suppressing the MEK/ERK signaling pathway in colorectal cancer

WEIWEI LI ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
ZHIFU YANG ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
LIKUN DING ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
YING WANG ; Department of Pharmacy, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi Province, 710032, China
XIAN ZHAO ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
JIANJIE CHU ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
QING JI ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
MINNA YAO ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China
JINGWEN WANG ; Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi Province, 710032, China

Abstract

Colorectal cancer (CRC) is one of the most common types of malignant cancers worldwide. Although molecularly targeted therapies have significantly improved treatment outcomes, most of these target inhibitors are resistant. Novel inhibitors as potential anti-cancer drug candidates are still needed to be discovered. Therefore, in the present study, we synthesized a novel 4-(1,3,4-thiadiazole-2-ylthio)pyrimidine derivative (compound 4) using fragment- and structure-based techniques and then investigated the anti-cancer effect and underlying mechanism of anti-CRC. The results revealed that compound 4 significantly inhibited HCT116 cell proliferation with IC50 values of 8.04 ± 0.94 µmol L–1 after 48 h and 5.52 ± 0.42 µmol L–1 after 72 h, respectively. Compound 4 also inhibited colony formation, migration, and invasion of HCT116 cells in a dose-dependent manner, as well as inducing cell apoptosis and arresting the cell cycle in the G2/M phase. In addition, compound 4 was able to inhibit the activation of the MEK/ERK signaling in HCT116 cells. And compound 4 yielded the same effects as the MEK inhibitor U0126 on cell apoptosis and MEK/ERK-related proteins. These findings suggested that compound 4 inhibited cell proliferation and growth, and induced cell apoptosis, indicating its use as e a novel and potent anti-cancer agent against CRC via the MEK/ERK signaling pathway.

Keywords

colorectal cancer; proliferation; apoptosis; metastasis; MEK/ERK signaling pathway

Hrčak ID:

303176

URI

https://hrcak.srce.hr/303176

Publication date:

30.9.2023.

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