2. Academic Validation
  3. β,β-Dimethylacrylalkannin, a key component of Zicao, induces cell cycle arrest and necrosis in hepatocellular carcinoma cells

β,β-Dimethylacrylalkannin, a key component of Zicao, induces cell cycle arrest and necrosis in hepatocellular carcinoma cells

  • Phytomedicine. 2024 Nov:134:155959. doi: 10.1016/j.phymed.2024.155959.
Li-Sha Shen 1,  Jia-Wen Chen 2,  Rui-Hong Gong 3,  Zesi Lin 4,  Yu-Shan Lin 5,  Xing-Fang Qiao 1,  Qian-Mei Hu 1,  Yong Yang 6,  Sibao Chen 7,  Guo-Qing Chen 8
Affiliations

Affiliations

  • 1 Chongqing Academy of Chinese Materia Medica, Chongqing 400065, PR China; Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, PR China.
  • 2 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, PR China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, PR China.
  • 3 Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., PR China.
  • 4 Southern Medical University Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Southern Medical University, Guangzhou 510315, PR China.
  • 5 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, PR China.
  • 6 Chongqing Academy of Chinese Materia Medica, Chongqing 400065, PR China; Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, PR China. Electronic address: yangychem@cqacmm.com.
  • 7 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, PR China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, PR China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., PR China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., PR China. Electronic address: sibao.chen@polyu.edu.hk.
  • 8 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, PR China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., PR China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., PR China. Electronic address: guoqing.chen@polyu.edu.hk.
PMID: 39178682 DOI: 10.1016/j.phymed.2024.155959
Abstract

Background: β,β-Dimethylacrylalkannin (DMAKN), a natural naphthoquinone found in Zicao, a traditional Chinese medicine (TCM), serves as the designated quantitative marker in the Chinese Pharmacopoeia. Despite its established role in assessing Zicao quality, DMAKN's biological potential remains underexplored in research.

Methods: We investigated DMAKN's involvement in Zicao's anti-hepatocellular carcinoma (HCC) properties using a combination of HPLC content analysis and comprehensive bioinformatics. Subsequently, both in vitro and in vivo experiments were conducted to evaluate DMAKN's efficacy against HCC. Mechanistic investigations focused on elucidating DMAKN's impact on cell cycle regulation and induction of cell death.

Results: Integrated HPLC analysis and bioinformatics identified DMAKN as the primary active compound responsible for Zicao's anti-HCC activity. In vitro and in vivo studies confirmed DMAKN's potent efficacy against HCC. Notably, DMAKN demonstrated dual effects on HCC cells: inhibiting proliferation at lower doses and inducing rapid cell death at higher doses. Mechanistic insights revealed that low-dose DMAKN induced G2/M phase cell cycle arrest through modulation of CDK1 and Cdc25C phosphorylation, while high-dose DMAKN triggered necrosis. Importantly, high-dose DMAKN caused a sharp increase in intracellular ROS levels in a short time, while low-dose DMAKN gradually increased ROS levels over a long period. Additionally, low-dose DMAKN-induced ROS activated the JNK pathway, crucial for cell cycle arrest, whereas high-dose DMAKN-induced necrosis was ROS-dependent but JNK-independent.

Conclusion: This study underscores DMAKN's pivotal role as the principal anti-HCC compound in Zicao, delineating its differential effects and underlying mechanisms. These results demonstrate the potential of DMAKN as a therapeutic agent for the treatment of HCC, providing important information for further study and advancement in Cancer therapy.

Keywords

Cell cycle; Hepatocellular carcinoma; Necrosis; Traditional Chinese medicine; Zicao; β,β-Dimethylacrylalkannin.

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