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
  • 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: [email protected].
  • 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: [email protected].
  • 8. School of Life and Environmental Sciences, Wenzhou University, Wenzhou 325000, China. Electronic address: [email protected].
  • 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: [email protected].
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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