Precision Medicine and Healthcare Research Center, Center for Biotechnology and Biomedicine, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, State Key Laboratory of Health Sciences and Technology, Tsinghua-Berkeley Shenzhen Institute (TBSI), Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
School of Life Sciences, Tsinghua University, Beijing 100084, China.
Int J Mol Sci. 2022 Nov 17;23(22):14217. doi: 10.3390/ijms232214217.
Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from has not been previously reported for its anticancer effects in HCC. This study aims to evaluate the inhibitory effects of MLD in HCC and explore the underlying mechanism. We found that the cell proliferation, DNA synthesis, and colony formation of HepG2 cells and the angiogenesis of HUVECs were all greatly inhibited by MLD. MLD caused mitochondrial damage and decreased the TOM20 expression and mitochondrial membrane potential, inducing ROS overproduction. Moreover, MLD promoted the cytochrome C from mitochondria into cytoplasm, leading to cleavage of caspase-9 and caspase-3 inducing GSDMD-related pyroptosis. In addition, we revealed that MLD activated mitophagy by inhibiting the PI3K/AKT/mTOR pathway. Using the ROS-scavenging reagent NAC, the activation effects of MLD on pyroptosis- and autophagy-related pathways were all inhibited. In the HepG2 xenograft model, MLD effectively inhibited tumor growth without detectable toxicities in normal tissue. In conclusion, MLD could be developed as a candidate drug for HCC treatment by inducing mitophagy and pyroptosis via promoting mitochondrial-related ROS production.
肝细胞癌（HCC）是原发性肝癌的主要亚型，死亡率很高。细胞焦亡和自噬是 HCC 病理生理学中的关键过程。寻找毒性更低的针对细胞焦亡和自噬的有效药物，对 HCC 的治疗很有帮助。马洛曲辛 D（MLD）是从 中分离得到的一种裂环烯醚萜类化合物，其在 HCC 中的抗癌作用尚未见报道。本研究旨在评价 MLD 对 HCC 的抑制作用，并探讨其作用机制。我们发现 MLD 可显著抑制 HepG2 细胞的增殖、DNA 合成和集落形成以及 HUVEC 的血管生成。MLD 导致线粒体损伤，降低 TOM20 表达和线粒体膜电位，诱导 ROS 过度产生。此外，MLD 促进线粒体中的细胞色素 C 进入细胞质，导致 caspase-9 和 caspase-3 的裂解，诱导 GSDMD 相关的细胞焦亡。此外，我们揭示 MLD 通过抑制 PI3K/AKT/mTOR 通路激活自噬。使用 ROS 清除剂 NAC，MLD 对与细胞焦亡和自噬相关的通路的激活作用均被抑制。在 HepG2 移植瘤模型中，MLD 有效抑制肿瘤生长，而对正常组织无明显毒性。总之，MLD 通过促进线粒体相关 ROS 的产生，诱导自噬和细胞焦亡，可能成为 HCC 治疗的候选药物。
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