A novel mechanism of 6-methoxydihydroavicine in suppressing ovarian carcinoma by disrupting mitochondrial homeostasis and triggering ROS/ MAPK mediated apoptosis

  • Front Pharmacol. 2023 May 5:14:1093650. doi: 10.3389/fphar.2023.1093650.
Huachang Zhang  1 ,  Fugen Shangguan  2 ,  Lan Zhang  3 ,  Nengfang Ma  4 ,  Shuling Song  5 ,  Li Ma  1 ,  Chuntong Liu  1 ,  Mengke Liu  1 ,  Jing An  6 ,  Hua Li  3 ,  Qizhi Cao  1
Affiliations
  • 1. Department of Immunology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, 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, China.
  • 3. The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China.
  • 4. School of Life and Environmental Sciences, Wenzhou University, Wenzhou, China.
  • 5. School of Gerontology, Binzhou Medical University, Yantai, Shandong, China.
  • 6. Division of Infectious Diseases and Global Health, School of Medicine, University of California San Diego (UCSD), La Jolla, CA, United States.
PMID: 37214469 DOI: 10.3389/fphar.2023.1093650
Abstract

Introduction: Alkaloids derived from M. cordata (Papaveraceae family), have been found to display antineoplastic activity in several types of Cancer. However, the antitumor effects and mechanisms of a new alkaloid extracted from the fruits of M. cordata, named 6-Methoxydihydroavicine (6-ME), remains unclear in the case of ovarian Cancer (OC). Methods: CCK-8 assay was employed to analyze the cell viabilities of OC cells. RTCA, and colony-formation assays were performed to measure OC cell growth. Alterations in Apoptosis and ROS levels were detected by flow cytometry in accordance with the instructions of corresponding assay kits. A Seahorse XFe96 was executed conducted to confirm the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect alterations in target proteins. The subcutaneous xenografted tumor model of OC was used to further validate the anti-tumor activity of 6-ME in vivo. Results: Here, we reported for the first time that 6-ME inhibits OC cells growth in vitro and in vivo. Meanwhile, we found that 6-ME showed great antineoplastic activities by disrupting mitochondria homeostasis and promoting Apoptosis in OC cells. Further investigation of the upstream signaling of Apoptosis revealed that 6-ME-triggered Apoptosis was induced by Reactive Oxygen Species (ROS)-mediated mitogen-activated protein kinase (MAPK) activation and mitochondria dysfunction in OC cells. Furthermore, we found oxaloacetic acid (OAA), a crucial metabolite has been proved to be related to NADPH production, can block the cytotoxicity and accumulation of ROS caused by 6-ME in OC cells. Discussion: In summary, our data show that 6-ME exhibits cytotoxicity to OC cells in a ROS-dependent manner by interrupting mitochondrial respiration homeostasis and inducing MAPK-mediated Apoptosis. This evidence suggests that 6-ME is a promising remedy for OC intervention.

Keywords
6-methoxydihydroavicine (6-ME); MAPK; mitochondria homeostasis; ovarian cancer (OC); oxaloacetic acid (OAA) metabolism; reactive oxygen species (ROS).
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