Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response.

IF 2.1 4区医学 Q2 BIOLOGY

International Journal of Radiation Biology Pub Date : 2023-01-01 DOI:10.1080/09553002.2022.2110326

Muzaffer Dukel, Kayahan Fiskin

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引用次数: 2

Abstract

Purpose: PAKs proteins are speculated as new promising targets for cancer therapy due to their central role in many oncogenic pathways. Because PAKs proteins are very significant during carcinogenesis, we aimed to investigate the hypothesis that inhibition of PAKs with IPA-3 and PF-3758309 treatment could synergistically reduce colon carcinoma cell growth.

Materials and methods: The cytotoxic effects of both drugs were determined by a cell viability assay. Cell cycle and apoptosis were analyzed by flow cytometry. The effects of inhibitor drugs on marker genes of apoptosis, autophagy, cell cycle, and DNA damage were tested via immunoblotting.

Results and conclusions: We found out the synergistic effect of these drugs in pair on five colon cancer cell lines. Combined treatment with IPA-3+PF-3758309 in SW620 and Colo 205 cells markedly suppressed colon formation and induced apoptosis, cell cycle arrest, and autophagy compared with treatment with each drug alone. Additionally, this combination sensitized colon cancer cells to ionizing radiation that resulted in inhibition of cell growth.

Significance: Collectively, our findings show for the first time that cotreatment of IPA-3 with PF-3758309 exhibits superior inhibitory effects on colon carcinoma cell growth via inducing DNA damage-related cell death and also enforces a cell cycle arrest.

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PAKs抑制剂IPA-3和PF-3758309联合使用可通过干扰DNA损伤反应有效抑制结肠癌细胞生长。

目的:PAKs蛋白在许多致癌途径中发挥核心作用，被推测为癌症治疗的新靶点。由于PAKs蛋白在癌变过程中非常重要，我们的目的是研究IPA-3和PF-3758309抑制PAKs是否可以协同抑制结肠癌细胞的生长。材料和方法:采用细胞活力法测定两种药物的细胞毒作用。流式细胞术分析细胞周期和凋亡情况。免疫印迹法检测抑制剂药物对细胞凋亡、自噬、细胞周期和DNA损伤标记基因的影响。结果与结论:我们发现了这些药物对5种结肠癌细胞系的协同作用。与单独用药相比，IPA-3+PF-3758309联合治疗SW620和Colo 205细胞可显著抑制结肠形成，诱导细胞凋亡、细胞周期阻滞和自噬。此外，这种组合使结肠癌细胞对电离辐射敏感，从而抑制细胞生长。意义:总的来说，我们的研究结果首次表明IPA-3与PF-3758309共处理通过诱导DNA损伤相关的细胞死亡对结肠癌细胞生长表现出卓越的抑制作用，并强制细胞周期阻滞。

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

International Journal of Radiation Biology 医学-核科学技术

CiteScore

5.00

自引率

11.50%

发文量

142

审稿时长

3 months

期刊介绍： The International Journal of Radiation Biology publishes original papers, reviews, current topic articles, technical notes/reports, and meeting reports on the effects of ionizing, UV and visible radiation, accelerated particles, electromagnetic fields, ultrasound, heat and related modalities. The focus is on the biological effects of such radiations: from radiation chemistry to the spectrum of responses of living organisms and underlying mechanisms, including genetic abnormalities, repair phenomena, cell death, dose modifying agents and tissue responses. Application of basic studies to medical uses of radiation extends the coverage to practical problems such as physical and chemical adjuvants which improve the effectiveness of radiation in cancer therapy. Assessment of the hazards of low doses of radiation is also considered.