阿司匹林代谢物 2,3-DHBA 和 2,5-DHBA 抑制癌细胞生长：对预防结直肠癌的影响。,Molecular Medicine Reports

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阿司匹林代谢物 2,3-DHBA 和 2,5-DHBA 抑制癌细胞生长：对预防结直肠癌的影响。
Molecular Medicine Reports ( IF 3.4 ) Pub Date : 2019-11-18 , DOI: 10.3892/mmr.2019.10822
Ranjini Sankaranarayanan ₁ , Chaitanya K Valiveti ₁ , Rakesh Dachineni ₁ , D Ramesh Kumar ₂ , Tana Lick ₁ , G Jayarama Bhat ₁

Affiliation

尽管关于阿司匹林治疗结直肠癌 (CRC) 的能力存在令人信服的证据，并且已经提出了许多理论和目标，但关于其作用机制尚未达成共识。在这方面，一个相对未探索的领域是阿司匹林代谢物 2,3-二羟基苯甲酸 (2,3-DHBA) 和 2,5-二羟基苯甲酸 (2,5-DHBA) 在其化学预防作用中所起的作用。在之前的一项研究中，我们证明 2,3-DHBA 和 2,5-DHBA 在体外抑制 CDK1 酶活性。本研究的目的是了解这些代谢物对所有参与细胞周期调节的 CDK（CDK 1、2、4 和 6）的酶活性的影响，以及它们对三种不同癌细胞系中克隆形成的影响. 此外，进行了计算机模拟研究以确定 2,3-DHBA 和 2,5-DHBA 与 CDK 相互作用的潜在位点。我们证明 2,3-DHBA 和 2,5-DHBA 从 500 µM 开始抑制 CDK-1 酶活性，而 CDK2 和 CDK4 活性仅在较高浓度 (>750 µM) 时被抑制。2,3-DHBA 从 250 µM 开始抑制 CDK6 酶活性，而 2,5-DHBA 抑制其活性 > 750 µM。集落形成分析表明，2,5-DHBA 在抑制 HCT-116 和 HT-29 CRC 细胞系（250-500 µM）以及 MDA-MB-231 乳腺癌细胞系（~100微米）。相比之下，2,3-DHBA 仅对 MDA-MB-231 细胞（~500 µM）有效。阿司匹林和水杨酸均未能抑制所有四种 CDK 和集落形成。根据目前的结果，建议 2,3-DHBA 和 2, 5-DHBA 可能有助于阿司匹林的化学预防特性，可能是通过抑制 CDK。目前的数据和提议的机制应该为未来的调查开辟新的领域。

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Aspirin metabolites 2,3‑DHBA and 2,5‑DHBA inhibit cancer cell growth: Implications in colorectal cancer prevention.

Although compelling evidence exists on the ability of aspirin to treat colorectal cancer (CRC), and numerous theories and targets have been proposed, a consensus has not been reached regarding its mechanism of action. In this regard, a relatively unexplored area is the role played by aspirin metabolites 2,3‑dihydroxybenzoic acid (2,3‑DHBA) and 2,5‑dihydroxybenzoic acid (2,5‑DHBA) in its chemopreventive actions. In a previous study, we demonstrated that 2,3‑DHBA and 2,5‑DHBA inhibited CDK1 enzyme activity in vitro. The aim of the present study was to understand the effect of these metabolites on the enzyme activity of all CDKs involved in cell cycle regulation (CDKs 1, 2, 4 and 6) as well as their effect on clonal formation in three different cancer cell lines. Additionally, in silico studies were performed to determine the potential sites of interactions of 2,3‑DHBA and 2,5‑DHBA with CDKs. We demonstrated that 2,3‑DHBA and 2,5‑DHBA inhibits CDK‑1 enzyme activity beginning at 500 µM, while CDK2 and CDK4 activity was inhibited only at higher concentrations (>750 µM). 2,3‑DHBA inhibited CDK6 enzyme activity from 250 µM, while 2,5‑DHBA inhibited its activity >750 µM. Colony formation assays showed that 2,5‑DHBA was highly effective in inhibiting clonal formation in HCT‑116 and HT‑29 CRC cell lines (250‑500 µM), and in the MDA‑MB‑231 breast cancer cell line (~100 µM). In contrast 2,3‑DHBA was effective only in MDA‑MB‑231 cells (~500 µM). Both aspirin and salicylic acid failed to inhibit all four CDKs and colony formation. Based on the present results, it is suggested that 2,3‑DHBA and 2,5‑DHBA may contribute to the chemopreventive properties of aspirin, possibly through the inhibition of CDKs. The present data and the proposed mechanisms should open new areas for future investigations.

更新日期：2019-11-01

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