Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
College of Chemical Engineering, Key Laboratory of Green Chemistry of Sichuan Institutes of Higher Education, Sichuan University of Science & Engineering, Zigong 643000, Sichuan, PR China.
Toxicol Appl Pharmacol. 2023 Nov 15;479:116729. doi: 10.1016/j.taap.2023.116729. Epub 2023 Oct 18.
Cancer cachexia is a systemic metabolic disorder syndrome characterized by severe wasting of muscle and adipose tissues while is lack of effective therapeutic approaches. Carnosol (CS) was found in our previous study to exhibit ameliorating effects on cancer cachexia. In the present study, we designed and synthesized 49 CS analogues by structural modification of CS. Results of activity screening revealed that, among the analogues, WK-63 exhibited better effects than CS in ameliorating atrophy of C2C12 myotubes induced by conditioned medium of C26 tumor cells. WK-63 could also dose-dependently alleviate adipocyte lipolysis of mature 3 T3-L1 cells induced by C26 tumor cell conditioned medium. WK-63 alleviated myotube atrophy by inhibiting Nuclear Factor kappa-B (NF-κB) and activating the Protein Kinase B (AKT) signaling pathway, and also alleviated fat loss by inhibiting NF-κB and Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways. Results of pharmacokinetic (PK) assay showed that, compared with other analogues, WK-63 exhibited longer half-life (T) and mean residence time (MRTs), as well as a larger concentration curve area (AUC). These findings suggested that WK-63 might exert optimal effects in vivo. In the C26 tumor-bearing mice model, administration of WK-63 ameliorated the body weight loss and also improved the weight loss of epididymal adipose tissue. WK-63 is expected to be a novel therapeutic option for the treatment of cancer cachexia.
癌症恶病质是一种以肌肉和脂肪组织严重消耗为特征的全身性代谢紊乱综合征，目前缺乏有效的治疗方法。我们之前的研究发现，卡诺醇（CS）对癌症恶病质有改善作用。在本研究中，我们通过 CS 的结构修饰设计并合成了 49 个 CS 类似物。活性筛选结果表明，在这些类似物中，WK-63 在改善 C26 肿瘤细胞条件培养基诱导的 C2C12 肌管萎缩方面比 CS 效果更好。WK-63 还可以剂量依赖性地减轻 C26 肿瘤细胞条件培养基诱导的成熟 3T3-L1 细胞脂肪细胞脂解。WK-63 通过抑制核因子 kappa-B（NF-κB）和激活蛋白激酶 B（AKT）信号通路来减轻肌管萎缩，通过抑制 NF-κB 和腺苷酸 5'-单磷酸（AMP）激活的蛋白激酶（AMPK）信号通路来减轻脂肪丢失。药代动力学（PK）测定结果表明，与其他类似物相比，WK-63 表现出更长的半衰期（T）和平均驻留时间（MRTs），以及更大的浓度曲线面积（AUC）。这些发现表明，WK-63 在体内可能发挥最佳效果。在 C26 荷瘤小鼠模型中，WK-63 的给药改善了体重减轻，也改善了附睾脂肪组织的体重减轻。WK-63 有望成为治疗癌症恶病质的一种新的治疗选择。
