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.
Alkaloids
/ pharmacology
Antineoplastic Agents
/ pharmacology
Caspases
/ metabolism
Cell Death
/ drug effects
Equol
/ analogs & derivatives
Humans
Oxaloacetic Acid
/ metabolism
Pancreatic Neoplasms
/ drug therapy
Papaveraceae
/ chemistry
Reactive Oxygen Species
/ metabolism
Receptor-Interacting Protein Serine-Threonine Kinases
/ metabolism
6-ME
OAA metabolism
PC intervention
PCD
RIPK1/caspases/GSDME
ROS
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
20 Jul 2022
20 Jul 2022
Historique:
received:
07
02
2022
revised:
04
05
2022
accepted:
10
05
2022
pubmed:
22
5
2022
medline:
15
6
2022
entrez:
21
5
2022
Statut:
ppublish
Résumé
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. The aim of this study was to investigate the anti-tumor effects of 6-ME on PC cells and the underlying mechanism. 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. 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. 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
The aim of this study was to investigate the anti-tumor effects of 6-ME on PC cells and the underlying mechanism.
METHODS
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 35597026
pii: S0944-7113(22)00242-2
doi: 10.1016/j.phymed.2022.154164
pii:
doi:
Substances chimiques
6-methoxyequol
0
Alkaloids
0
Antineoplastic Agents
0
Reactive Oxygen Species
0
Oxaloacetic Acid
2F399MM81J
Equol
531-95-3
RIPK1 protein, human
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
154164Informations de copyright
Copyright © 2022 Elsevier GmbH. All rights reserved.