AUTHOR=Zhang Huachang , Shangguan Fugen , Zhang Lan , Ma Nengfang , Song Shuling , Ma Li , Liu Chuntong , Liu Mengke , An Jing , Li Hua , Cao Qizhi 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1093650

DOI=10.3389/fphar.2023.1093650

ISSN=1663-9812

ABSTRACT=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 fruits, named 6-Methoxydihydroavicine (6-ME), remains unclear in the case of ovarian cancer (OC). Here, we reported for the first time that 6-ME exhibits 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 MAPK activation and mitochondria dysfunction in OC cells. Disturbance of oxaloacetic acid (OAA) metabolism, a crucial metabolite that has been shown abled to counteract the cytotoxicity by 6-ME in this study, leads to deficiency of OAA, thereby causing accumulation of ROS levels by eliminating NADPH content. 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.