纳米粒系统提高了法呢基二磷酸法呢基转移酶 4 抑制剂（artocarpin）的溶解度，从而增强了其在人肝癌细胞中的自噬活性。
Enhanced autophagic activity of artocarpin in human hepatocellular carcinoma cells through improving its solubility by a nanoparticle system.
机构信息
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Department of Medical Imaging, Chi Mei Medical Center, Tainan, Taiwan, ROC; Department of Medical Imaging and Radiological Science, College of Health Sciences, Central Taiwan University of Science and Technology, Taichung City, Taiwan, ROC.
出版信息
Phytomedicine. 2016 May 15;23(5):528-40. doi: 10.1016/j.phymed.2016.02.010. Epub 2016 Mar 2.
BACKGROUND
Hepatocellular carcinoma (HCC) is the most common liver cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Natural products offer great resources of developing new and effective chemopreventive or chemotherapeutic agents. Artocarpus communis extracts and its active constituent, prenylated flavonoid artocarpin induce human hepatocellular carcinoma cell death. However, the poor water solubility drawbacks of artocarpin restrict its clinical application and bioavailability.
PURPOSE
This study developed the artocarpin nanoparticle system to overcome the poor water solubility drawbacks and investigated the improvement of therapeutic efficacy of artocarpin by adopting novel nanoparticle delivery strategy.
METHODS
Antiproliferative activity of artocarpin was evaluated by MTT assay. Cell morphology observation by microscope, DNA fragmentation assay, cell cycle analysis, Annexin V apoptosis cell staining, monodansylcadaverine and acridine orange staining and immunoblot analysis were used to evaluate the induction of autophagy by artocarpin. The determination of particle size, amorphous transformation, hydrogen-bond formation, yield, encapsulation efficiency and the solubility study were used to investigate the solubility enhancement mechanism of artocarpin.
RESULTS
The present study demonstrates that the anticancer effect of artocarpin in HepG2 and PLC/PRF/5 hepatoma cells is mediated through the autophagic cell death mechanism. Results also demonstrated that artocarpin nanoparticles enhanced the solubility of artocarpin by reducing particle size, transforming high energy amorphous state, and forming hydrogen bond with excipients. Additionally, ArtN exhibited better autophagic cytotoxicity compared to free artocarpin.
CONCLUSION
This work reveals the antihepatoma activity of artocarpin by inducing autophagic cell death and the improvement of therapeutic efficacy of artocarpin by adopting novel nanoparticle delivery strategy. The research provided a basis of ArtN could be explored as a low-dose alternative of artocarpin in anticancer treatment and research applications.
背景
肝细胞癌（HCC）是全球最常见的肝癌，预后不良且对化疗有耐药性。因此，新型癌症治疗方法具有重要意义。天然产物为开发新的有效化学预防或化学治疗药物提供了丰富的资源。面包果提取物及其有效成分，烯丙基化黄酮类化合物 artocarpin 诱导人肝癌细胞死亡。然而，artocarpin 的水溶性差限制了其临床应用和生物利用度。
目的
本研究开发了 artocarpin 纳米颗粒系统以克服水溶性差的缺点，并通过采用新型纳米颗粒递药策略来提高 artocarpin 的治疗效果。
方法
采用 MTT 法评价 artocarpin 的抗增殖活性。通过显微镜观察细胞形态、DNA 片段化分析、细胞周期分析、Annexin V 凋亡细胞染色、单丹磺酰尸胺和吖啶橙染色和免疫印迹分析来评估 artocarpin 诱导自噬的作用。通过测定粒径、无定形转化、氢键形成、产率、包封效率和溶解度研究来研究 artocarpin 溶解度增强的机制。
结果
本研究表明，artocarpin 在 HepG2 和 PLC/PRF/5 肝癌细胞中的抗癌作用是通过自噬细胞死亡机制介导的。结果还表明，artocarpin 纳米颗粒通过减小粒径、转化高能无定形状态和与赋形剂形成氢键来提高 artocarpin 的溶解度。此外，ArtN 比游离 artocarpin 具有更好的自噬细胞毒性。
结论
本研究揭示了 artocarpin 通过诱导自噬细胞死亡发挥抗肝癌作用，并通过采用新型纳米颗粒递药策略提高 artocarpin 的治疗效果。该研究为 ArtN 作为 artocarpin 的低剂量替代物在癌症治疗和研究应用中的探索提供了依据。
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