WEE Family Kinase Inhibitors Combined with Sorafenib Can Selectively Inhibit HCC Cell Proliferation.

IF 2.3 4区医学 Q3 ONCOLOGY

Current cancer drug targets Pub Date : 2024-06-10 DOI:10.2174/0115680096298370240520093003

Anling Chen, Ke Yin, Yu Liu, Lei Hu, Qianwen Cui, Xiaofeng Wan, Wulin Yang

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引用次数: 0

Abstract

Background: Sorafenib is currently the first choice for the treatment of patients with advanced hepatocellular carcinoma, but its therapeutic effect is still limited.

Objectives: This study aims to examine whether WEE family kinase inhibitors can enhance the anticancer effect of sorafenib.

Methods: We analyzed the expression levels of PKMYT1 kinase and WEE1 kinase in HCC, studied the inhibitory effect of PKMYT1 kinase inhibitor RP-6306, WEE1 kinase inhibitor adavosertib combined with sorafenib on the proliferation of HCC cells, and detected the effect of drug combination on CDK1 phosphorylation.

Results: We found that PKMYT1 and WEE1 were upregulated in HCC and were detrimental to patient survival. Cell experiments showed that both RP-6306 and adavosertib (1-100 μM) inhibited the proliferation of HCC cell lines in a dose-dependent manner alone, and the combination of the two drugs had a synergistic effect. In HCC cell lines, sorafenib combined with RP-6306 or adavosertib showed a synergistic antiproliferation effect and less toxicity to normal cells. Sorafenib combined with RP-6306 and adavosertib further inhibited the proliferation of HCC cells and caused complete dephosphorylation of CDK1.

Conclusion: Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.

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WEE 家族激酶抑制剂联合索拉非尼可选择性抑制 HCC 细胞增殖

背景：索拉非尼是目前治疗晚期肝细胞癌患者的首选药物，但其治疗效果仍然有限：索拉非尼是目前治疗晚期肝细胞癌患者的首选药物，但其治疗效果仍然有限：本研究旨在探讨WEE家族激酶抑制剂能否增强索拉非尼的抗癌效果：我们分析了PKMYT1激酶和WEE1激酶在HCC中的表达水平，研究了PKMYT1激酶抑制剂RP-6306、WEE1激酶抑制剂adavosertib联合索拉非尼对HCC细胞增殖的抑制作用，并检测了联合用药对CDK1磷酸化的影响：结果：我们发现PKMYT1和WEE1在HCC中上调，并对患者的生存不利。细胞实验表明，RP-6306 和 adavosertib（1-100 μM）单独使用对 HCC 细胞株的增殖有剂量依赖性抑制作用，两种药物联合使用有协同作用。在 HCC 细胞系中，索拉非尼与 RP-6306 或 adavosertib 联用具有协同抗增殖作用，对正常细胞的毒性较小。索拉非尼联合 RP-6306 和 adavosertib 可进一步抑制 HCC 细胞的增殖，并导致 CDK1 完全去磷酸化：综上所述，我们的研究结果为今后索拉非尼联合 RP-6306 或 adavosertib 治疗 HCC 提供了实验证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current cancer drug targets 医学-肿瘤学

CiteScore

5.40

自引率

0.00%

发文量

105

审稿时长

1 months

期刊介绍： Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.