Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma

IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Piao Luo , Qian Zhang , Shuo Shen , Yehai An , Lixia Yuan , Yin-Kwan Wong , Sizhe Huang , Shaohui Huang , Jingnan Huang , Guangqing Cheng , Jiahang Tian , Yu Chen , Xiaoyong Zhang , Weiguang Li , Songqi He , Jigang Wang , Qingfeng Du
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Abstract

Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the Tripterygium wilfordii 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.

Abstract Image

雷公桃红素脂质体直接靶向VDAC2诱导肝癌细胞铁下垂和凋亡的机制工程
肝细胞癌(HCC)是最常见和最致命的恶性肿瘤之一。雷公藤红素(Celastrol)是一种从雷公藤植物中提取的天然产物,因其抗癌的潜在功效而被广泛研究。但其作用机制尚不明确,阻碍了其临床应用。在这里,我们使用化学蛋白质组学来确定细胞的直接靶点,并通过在HCC中开发基于细胞的脂质体来增强其靶向性和抗肿瘤能力。我们证明了细胞选择性地靶向电压依赖性阴离子通道2 (VDAC2)。细胞直接与VDAC2的半胱氨酸残基结合,并通过VDAC2介导的线粒体通透性过渡孔(mPTP)功能失调诱导细胞色素C释放。我们进一步发现,细胞诱导ros介导的肝癌细胞铁下垂和凋亡。此外,将细胞共包被烷基葡萄糖苷修饰脂质体(AGCL)提高了其抗肿瘤效果,并将其副作用降至最低。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,促进细胞凋亡。我们的研究结果表明,细胞直接靶向VDAC2诱导线粒体依赖性细胞死亡,而细胞脂质体增强了其靶向性并减少了副作用。总之,细胞显示出作为HCC治疗药物的前景。
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来源期刊
Asian Journal of Pharmaceutical Sciences
Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
18.30
自引率
2.90%
发文量
11
审稿时长
14 days
期刊介绍: The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.
文献相关原料
公司名称 产品信息 采购帮参考价格
上海源叶 Celastrol
¥32.00~¥52828.00
上海源叶 N-octyl ?2-D-glucopyranoside
¥1770.00~¥13800.00
上海源叶 N-octyl ?2-D-glucopyranoside
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