Flavokawain a通过cdt1依赖性p27调控诱导细胞周期阻滞,并与venetoclax协同治疗急性髓系白血病。

IF 3.3 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Lili Jin , Xia Jiang , Youhong Li , Sumeng Xiang , Renzhi Pei , Ying Lu , Lei Jiang
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引用次数: 0

摘要

急性髓性白血病(AML)患者预后不良的主要原因是缺乏持续有效的治疗方法。尽管最近批准了靶向药物,如BCL-2抑制剂venetoclax,但由于耐药性的发展,临床获益有限。使用天然产物正在成为治疗包括急性髓性白血病在内的恶性疾病的可行策略。黄卡蛋白A (Flavokawain A, FKA)是从卡瓦根中提取的天然查尔酮,具有广泛的抗肿瘤活性。FKA在AML中的治疗潜力尚不清楚。在目前的研究中,我们发现用FKA治疗以剂量和时间依赖的方式降低了四种AML细胞系的生存能力。FKA可显著增强venetoclax的抗aml活性。在机制上,FKA诱导AML细胞G1期阻滞,同时CDT1下调和p27上调。敲低CDT1增加p27的表达,导致细胞活力受到抑制。FKA引起的p27上调和活力抑制均可通过CDT1过表达部分恢复。FKA单独或联合venetoclax的治疗效果在AML患者的原代细胞中得到验证,进一步加强了本研究的临床相关性。因此,我们的数据表明,FKA可以被认为是治疗AML的潜在治疗剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Flavokawain a induces cell cycle arrest through CDT1-dependent p27 regulation and synergizes with venetoclax in acute myeloid leukemia

Flavokawain a induces cell cycle arrest through CDT1-dependent p27 regulation and synergizes with venetoclax in acute myeloid leukemia
The poor prognosis of patients with acute myeloid leukemia (AML) is largely ascribed to the deficiency of persistently effective therapies. Despite the recent approval of targeted drugs such as the BCL-2 inhibitor venetoclax, the clinical benefit is limited due to the development of resistance. The use of natural products is emerging as a feasible strategy to treat malignant diseases including AML. Flavokawain A (FKA) is a naturally occurring chalcone isolated from the root of kava and possesses extensive antitumor activities. The therapeutic potential of FKA in AML remains unknown. In the present study, we found that treatment with FKA reduced the viability in four AML cell lines in dose- and time-dependent manners. The anti-AML activity of venetoclax was significantly potentiated by FKA. Mechanistically, FKA induced G1 phase arrest in AML cells along with CDT1 downregulation and p27 upregulation. Knockdown of CDT1 increased the expression of p27, leading to the inhibition on cell viability. Both p27 upregulation and viability inhibition caused by FKA was partially rescued by CDT1 overexpression. The therapeutic effect of FKA alone or in combination with venetoclax was verified in primary blasts from AML patients, further strengthening the clinical relevance of the current study. Therefore, our data suggest that FKA can be considered as a potential therapeutic agent in the treatment of AML.
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来源期刊
CiteScore
6.80
自引率
2.60%
发文量
309
审稿时长
32 days
期刊介绍: Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.
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