Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Biomed Pharmacother. 2021 Aug;140:111737. doi: 10.1016/j.biopha.2021.111737. Epub 2021 May 18.
Guggulsterone (GS) [4,17(20)-pregnadiene-3,16-dione], is the main active phytosterol constituent in guggul, the gum resin of Commiphora wightii (Arnott.) Bhand./Commiphora mukul Engl. tree, and is known for its medicinal effects. In this study, we report that GSD-1, a structurally-related synthetic GS derivative, strongly inhibits NF-κB activation induced by TNF-α. GSD-1 prevented the nuclear translocation of p65 through the blockade of IκBα degradation and p65 phosphorylation, and further inhibited the activation of upstream kinases, including transforming growth factor-β activated kinase 1 (TAK1), IκB kinase (IKK) α, and IKKβ. Furthermore, GSD-1 inhibited the cell-intrinsic activation of NF-κB, and exerted its direct anti-cancer and anti-metastatic effects in both murine and human breast cancer cell lines. This study demonstrated GSD-1 to be an attractive compound to target NF-κB activation that has potential for treating breast cancer growth and metastasis.
古卡胶素（GS）[4,17(20)-孕二烯-3,16-二酮]是古卡树（ Commiphora wightii （Arnott.） Bhand. / Commiphora mukul Engl.）胶脂中的主要活性植物甾醇成分，具有药用功效。在这项研究中，我们报告了一种结构相关的合成 GS 衍生物 GSD-1，它可强烈抑制 TNF-α诱导的 NF-κB 激活。GSD-1 通过阻止 IκBα降解和 p65 磷酸化，阻止了 p65 的核易位，进一步抑制了上游激酶的激活，包括转化生长因子-β激活激酶 1（TAK1）、IκB 激酶（IKK）α和 IKKβ。此外，GSD-1 抑制了 NF-κB 的细胞内激活，并在鼠源和人源乳腺癌细胞系中发挥了直接的抗癌和抗转移作用。这项研究表明 GSD-1 是一种有吸引力的靶向 NF-κB 激活的化合物，有望用于治疗乳腺癌的生长和转移。
