Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China; School of Medicine, Shanghai Jiao tong University, Shanghai, 200240, PR China.
Department of Pharmacy, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China.
J Ethnopharmacol. 2020 Oct 5;260:113066. doi: 10.1016/j.jep.2020.113066. Epub 2020 Jun 4.
Salvia miltiorrhiza bunge (Danshen) has been extensively used to treat a wide variety of diseases including cancers. Cryptotanshinone is a major lipophilic compound extracted from the root of Danshen and has been reported to exert various pharmacological effects, however, its anti-cachectic remains unknown.
The present study aims to investigate the anti-cachectic efficacy of cryptotanshinone and elucidate the underlying mechanism.
Prevention of muscle wasting by cryptotanshinone in colon adenocarcinoma CT26-induced cachexia and CT26 conditioned medium (TCM)-induced myotubes were investigated. Main features of cancer cachexia were determined after cryptotanshinone administration. The therapeutic effect of cryptotanshinone on myotube atrophy was assessed by morphological observation and myotube fiber width determination. E3 ubiquitin ligases muscle RING-finger containing protein 1 (MuRF1) and muscle atrophy Fbox protein (MAFbx/Atrogin-1) expression and STAT3 activation were examined using western blot, real-time qPCR and dual-luciferase reporter gene assays both in vitro and in vivo. The myotubes were infected with lentiviruses expressing STAT3 or GFP.
In CT26 tumor-bearing mice, cryptotanshinone (20 and 60 mg/kg) administration drastically prevented systemic cancer cachexia from whole body weight loss and wasting of multiple tissues including heart, fat and skeletal muscle, with a negligible effect on cancer growth at dose of 20 mg/kg cryptotanshinone administration prevented the induction of MuRF1 and MAFbx/Atrogin-1 in cachectic muscles. Moreover, cryptotanshinone (2.5-10 μM) dose-dependently reduced the elevated expression of MuRF1 and MAFbx/Atrogin-1 in C2C12 myotubes, and improved myotube atrophy. We showed that cryptotanshinone significantly suppressed the hyper-activated STAT3 in cachectic muscles and C2C12 myotubes and inhibited STAT3 transcriptional activity, but it did not repress the activation of STAT1. The inhibitory effect of cryptotanshinone on TCM-induced myotube atrophy was blocked by STAT3 overexpression.
These data suggest that cryptotanshinone prevents muscle wasting in cancer cachexia through STAT3 inhibition, and it may be a promising candidate drug for the treatment of cancer cachexia.
丹参（丹参）已被广泛用于治疗各种疾病，包括癌症。隐丹参酮是从丹参根部提取的主要亲脂性化合物，已被报道具有多种药理作用，但其抗恶病质作用尚不清楚。
本研究旨在探讨隐丹参酮的抗恶病质作用，并阐明其潜在机制。
研究了隐丹参酮在结肠腺癌 CT26 诱导的恶病质和 CT26 条件培养基（TCM）诱导的肌管中预防肌肉萎缩的作用。在隐丹参酮给药后，确定了恶病质的主要特征。通过形态学观察和肌管纤维宽度测定评估隐丹参酮对肌管萎缩的治疗作用。使用 Western blot、实时 qPCR 和双荧光素酶报告基因检测，在体外和体内检测 E3 泛素连接酶肌肉环指蛋白 1（MuRF1）和肌肉萎缩 F 盒蛋白（MAFbx/Atrogin-1）的表达和 STAT3 激活。肌管用表达 STAT3 或 GFP 的慢病毒感染。
在 CT26 荷瘤小鼠中，隐丹参酮（20 和 60mg/kg）给药可显著防止全身恶病质引起的全身体重减轻和心脏、脂肪和骨骼肌等多种组织的消耗，而在 20mg/kg 隐丹参酮给药剂量下对癌症生长几乎没有影响，可防止恶病质肌肉中 MuRF1 和 MAFbx/Atrogin-1 的诱导。此外，隐丹参酮（2.5-10μM）剂量依赖性地降低 C2C12 肌管中升高的 MuRF1 和 MAFbx/Atrogin-1 的表达，并改善肌管萎缩。我们表明，隐丹参酮可显著抑制恶病质肌肉和 C2C12 肌管中过度激活的 STAT3，并抑制 STAT3 转录活性，但不抑制 STAT1 的激活。STAT3 过表达阻断了隐丹参酮对 TCM 诱导的肌管萎缩的抑制作用。
这些数据表明，隐丹参酮通过抑制 STAT3 预防癌症恶病质中的肌肉消耗，它可能是治疗癌症恶病质的有前途的候选药物。
