Sambutoxin, a representative derivative of 4-hydroxy-2-pyridone, was isolated from Hericium alpestre for the first time in this study. The possible correlation between the sambutoxin-induced suppression of tumor growth and its influence on cell-cycle arrest and apoptosis was investigated. The effects of sambutoxin on reactive oxygen species (ROS) production, DNA damage, mitochondrial transmembrane potential, cell apoptosis, and the expression of related proteins were evaluated. An in vitro cell viability study demonstrated that sambutoxin could inhibit the proliferation of various cancer cells. Treatment with sambutoxin induced the production of ROS, which caused DNA damage. Furthermore, the subsequent sambutoxin-induced activation of ATM and Chk2 resulted in G2/M arrest, accompanied by decreased expression of cdc25C, cdc2, and cyclin B1. Sambutoxin induced apoptosis by activating the mitochondrial apoptosis pathway through an increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (ΔΨm), cytochrome (Cyt) c release, caspase-9 and caspase-3 activation, and poly(ADP–ribose) polymerase (PARP) degradation. The ROS elevation induced the sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, a JNK inhibitor, nearly completely reversed sambutoxin-induced apoptosis. Accordingly, an in vivo study showed that sambutoxin exhibited potential antitumor activity in a BALB/c nude mouse xenograft model without significant systemic toxicity. Moreover, the expression changes in proteins related to the G2/M phase, DNA damage, and apoptosis in vivo were consistent with those in vitro. Importantly, sambutoxin has remarkable antiproliferative effects and is a promising anticarcinogen candidate for cancer treatment.

中文翻译：

---

发现和表征4-羟基-2-吡啶酮衍生物三丁氧基辛醇作为有力和有望的抗癌药物候选物：活性和分子机理

从猴头猴中分离出4-丁-2-吡啶酮的代表性衍生物三丁氧辛这项研究中的第一次。考察了由sambutoxin诱导的肿瘤生长抑制与其对细胞周期阻滞和凋亡的影响之间的可能相关性。评估了sambutoxin对活性氧（ROS）产生，DNA损伤，线粒体跨膜电位，细胞凋亡以及相关蛋白表达的影响。一项体外细胞生存力研究表明，三丁氧还蛋白可以抑制各种癌细胞的增殖。用三丁氧还蛋白处理可诱导产生ROS，从而引起DNA损伤。此外，随后的由sambutoxin诱导的ATM和Chk2激活导致G2 / M阻滞，并伴有cdc25C，cdc2和细胞周期蛋白B1的表达降低。Sambutoxin通过增加Bax / Bcl-2比，激活线粒体膜电位（ΔΨm），细胞色素（Cyt）c释放，caspase-9和caspase-3活化以及多聚（ADP-核糖）激活线粒体凋亡途径，从而诱导细胞凋亡。 ）聚合酶（PARP）降解。ROS升高诱导c-Jun N端激酶（JNK）持续磷酸化，而JNK抑制剂SP600125几乎完全逆转了sambutoxin诱导的细胞凋亡。因此，体内研究表明，三丁氧还蛋白在BALB / c裸鼠异种移植模型中显示出潜在的抗肿瘤活性，而没有明显的全身毒性。此外，体内与G2 / M期，DNA损伤和细胞凋亡相关的蛋白质表达变化与体外表达一致。重要的，