State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Bioorg Chem. 2021 Jul;112:104963. doi: 10.1016/j.bioorg.2021.104963. Epub 2021 May 5.
Pseudolaric acid A (PAA), one of the main bioactive ingredients in traditional medicine Pseudolarix cortex, exhibits remarkable anticancer activities. Yet its mechanism of action and molecular target have not been investigated and remain unclear. In this work, mechanistic study showed that PAA induced cell cycle arrest at G2/M phase and promoted cell death through caspase-8/caspase-3 pathway, demonstrating potent antiproliferation and anticancer activities. PAA was discovered to be a new Hsp90 inhibitor and multiple biophysical experiments confirmed that PAA directly bind to Hsp90. Active PAA-probe was designed, synthesized and biological evaluated. It was subsequently employed to verify the cellular interaction with Hsp90 in HeLa cells through photoaffinity labeling approach. Furthermore, NMR experiments showed that N-terminal domain of Hsp90 and essential groups in PAA are important for the protein-inhibitor recognition. Structure-activity relationship studies revealed the correlation between its Hsp90 inhibitory activity with anticancer activity. This work proposed a potential mechanism involved with the anticancer activity of PAA and will improve the appreciation of PAA as a potential cancer therapy candidate.
土槿皮乙酸（PAA）是传统中药土槿皮的主要生物活性成分之一，具有显著的抗癌活性。然而，其作用机制和分子靶点尚未得到研究，仍不清楚。在这项工作中，机制研究表明，PAA 通过 caspase-8/caspase-3 途径诱导细胞周期停滞在 G2/M 期，并促进细胞死亡，表现出很强的增殖抑制和抗癌活性。发现 PAA 是一种新的 HSP90 抑制剂，多种生物物理实验证实 PAA 直接与 HSP90 结合。设计、合成并生物评价了活性 PAA 探针。随后，通过光亲和标记法将其用于验证 HeLa 细胞中与 HSP90 的细胞相互作用。此外，NMR 实验表明，Hsp90 的 N 端结构域和 PAA 中的必需基团对于蛋白质-抑制剂的识别是重要的。构效关系研究揭示了其 HSP90 抑制活性与抗癌活性之间的相关性。这项工作提出了 PAA 抗癌活性的潜在机制，并将提高对 PAA 作为潜在癌症治疗候选药物的认识。
