2. Academic Validation
  3. 6-methoxydihydroavicine, the alkaloid extracted from Macleaya cordata (Willd.) R. Br. (Papaveraceae), triggers RIPK1/Caspase-dependent cell death in pancreatic cancer cells through the disruption of oxaloacetic acid metabolism and accumulation of reactive oxygen species

6-methoxydihydroavicine, the alkaloid extracted from Macleaya cordata (Willd.) R. Br. (Papaveraceae), triggers RIPK1/Caspase-dependent cell death in pancreatic cancer cells through the disruption of oxaloacetic acid metabolism and accumulation of reactive oxygen species

  • Phytomedicine. 2022 Jul 20;102:154164. doi: 10.1016/j.phymed.2022.154164.
Nengfang Ma 1,  Fugen Shangguan 2,  Hongfei Zhou 3,  Huimin Huang 4,  Jun Lei 5,  Jing An 6,  Guihua Jin 3,  Weiwei Zhuang 3,  Shipeng Zhou 3,  Shijia Wu 3,  Hongping Xia 7,  Hailong Yang 8,  Linhua Lan 9
Affiliations

Affiliations

  • 1 School of Life and Environmental Sciences, Wenzhou University, Wenzhou 325000, China; Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 2 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: mgsgfg2019@wmu.edu.cn.
  • 3 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 4 School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, University Town, Ouhai District, Wenzhou 325000, China.
  • 5 State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 6 Division of Infectious Diseases and Global Health, School of Medicine, University of California San Diego (UCSD), LaJolla, CA 92037, United States of America.
  • 7 Henan Medical School & Huaihe Hospital & The First Affiliated Hospital, Henan University, Kaifeng, China. Electronic address: xiahongping@njmu.edu.cn.
  • 8 School of Life and Environmental Sciences, Wenzhou University, Wenzhou 325000, China. Electronic address: yhl@wzu.edu.cn.
  • 9 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: paullee90@wmu.edu.cn.
PMID: 35597026 DOI: 10.1016/j.phymed.2022.154164
Abstract

Background: Many extracts and purified Alkaloids of M. cordata (Papaveraceae family) have been reported to display promising anti-tumor effects by inhibiting Cancer cell growth and inducing Apoptosis in many Cancer types. However, no evidence currently exists for anti-pancreatic Cancer activity of Alkaloids extracted from M. cordata, including a novel alkaloid named 6‑methoxy dihydrosphingosine (6-Methoxydihydroavicine, 6-ME) derived from M. cordata fruits.

Purpose: The aim of this study was to investigate the anti-tumor effects of 6-ME on PC cells and the underlying mechanism.

Methods: CCK-8, RTCA, and colony-formation assays were used to analyze PC cell growth. Cell death ratios, changes in MMP and ROS levels were measured by flow cytometry within corresponding detection kits. A Seahorse XFe96 was employed to examine the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect changes in target molecules.

Results: 6-ME effectively reduced the growth of PC cells and promoted PCD by activating RIPK1, caspases, and GSDME. Specifically, 6-ME treatment caused a disruption of OAA metabolism and increased ROS production, thereby affecting mitochondrial homeostasis and reducing aerobic glycolysis. These responses resulted in Mitophagy and RIPK1-mediated cell death.

Conclusion: 6-ME exhibited specific anti-tumor effects through interrupting OAA metabolic homeostasis to trigger ROS/RIPK1-dependent cell death and mitochondrial dysfunction, suggesting that 6-ME could be considered as a highly promising compound for PC intervention.

Keywords

6-ME; OAA metabolism; PC intervention; PCD; RIPK1/caspases/GSDME; ROS.

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