Luo Piao, Zhang Qian, Shen Shuo, An Yehai, Yuan Lixia, Wong Yin-Kwan, Huang Sizhe, Huang Shaohui, Huang Jingnan, Cheng Guangqing, Tian Jiahang, Chen Yu, Zhang Xiaoyong, Li Weiguang, He Songqi, Wang Jigang, Du Qingfeng
School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Asian J Pharm Sci. 2023 Nov;18(6):100874. doi: 10.1016/j.ajps.2023.100874. Epub 2023 Nov 30.
Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC.
肝细胞癌（HCC）是最常见且致命的恶性肿瘤之一。雷公藤红素（Cel）是一种从植物中提取的天然产物，其抗癌潜在功效已得到广泛研究。然而，其作用机制尚不明确，这阻碍了它的临床应用。在此，我们运用化学蛋白质组学来鉴定Cel的直接靶点，并通过开发基于Cel的脂质体来增强其靶向性和抗肿瘤能力，用于肝癌治疗。我们证明Cel选择性靶向电压依赖性阴离子通道2（VDAC2）。Cel直接与VDAC2的半胱氨酸残基结合，并通过失调VDAC2介导的线粒体通透性转换孔（mPTP）功能诱导细胞色素C释放。我们进一步发现Cel在肝癌细胞中诱导活性氧（ROS）介导的铁死亡和凋亡。此外，将Cel共包封到烷基糖苷修饰的脂质体（AGCL）中可提高其抗肿瘤功效并将副作用降至最低。AGCL已被证明能有效抑制肿瘤细胞的增殖。在异种移植裸鼠实验中，AGCL显著抑制肿瘤生长并促进凋亡。我们的研究结果表明，Cel直接靶向VDAC2以诱导线粒体依赖性细胞死亡，而Cel脂质体增强了其靶向性并减少了副作用。总体而言，Cel有望成为肝癌的治疗药物。
