Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils
Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils
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DOI：
10.2174/1871520617666170327105706
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发表时间：
2018-01-01
影响因子：
2.8
通讯作者：
Narzary, Bardwi
中科院分区：
文献类型：
--
作者：
Bordoloi, Manobjyoti;Saikia, Surovi;Narzary, Bardwi
背景：根据世界卫生组织的报告，癌症是世界上一个严重的健康问题，全球癌症负担每年增加到1400万新病例，其中820万人死亡，预计在未来20年将增加70%。这些稳步上升的死亡对快速发展的抗癌药物的需求。近年来，精油作为一种天然的多组分复杂体系，在寻找新型抗癌药物方面引起了人们的广泛关注。材料和方法：评估精油成分的药物属性，特别是对COX、5-LOX、AKT、MDM2、PDK1和mTOR的亲和力，mTOR定义了磷脂酰肌醇-3激酶（PI3K）途径。研究人员分析了不同植物精油中存在的123种化合物的药物属性，然后允许这些化合物与PI3K依赖性受体对接，这些受体对恶性肿瘤的发展至关重要。其中21个化合物具有高药物相似性，主要细胞色素p450异构体具有良好的代谢作用。最后，利用结合亲和力最高的最佳对接化合物构建配体基药效团。作为p -糖蛋白的抑制剂，这些分子也表现出良好的吸收谱和非致癌特性。此外，从这21个化合物中，有6个化合物对A549肺癌细胞进行了评价。结果：所获得的药效特性可用于从精油化合物中特异性设计和筛选磷脂酰肌醇-3激酶途径活性抑制剂的部分，最终的21种化合物可进一步推广到抗癌药物开发的研究中。其中，6种化合物对A549肺癌细胞表现出良好的抑制效果。此外，免疫印迹分析证实了化合物对mTOR和AKT酶的抑制作用，这些酶是pi3k途径下游信号传导的主控酶。结论：壬酸甲酯、(R)-香茅醇、顺式卡维罗（l-卡维罗）、3-甲基-环己酮、4-蒈烯和叔叶皂烯等化合物挥发性强，可作为PI3K靶向抗癌药物直接应用于肺癌的吸入剂或喷雾剂。
Background: Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO. These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents.Materials and Methods: The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3-kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and non-carcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells.Results: The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway.Conclusion: Methyl nonanoate, (R)-citronellol, cis-carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile.