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

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

“…To investigate this hypothesis, we cultured OC cells with 6-ME in the presence or absence of OAA (a crucial metabolite of the TCA cycle), which has been demonstrated to modulate the homeostasis of mitochondrial function (Desideri et al, 2015;Martinez-Reyes and Chandel, 2020). We thus confirmed that OAA, rather than other metabolites, can eliminate the cytotoxicity caused by 6-ME in OC cells (Figure 6A), which was consistent with our latest results regarding the effects of 6-ME and OAA on pancreatic cancer (Ma et al, 2022). The deficiency of OAA has been verified to contribute to the impairment of the balance of NADPH generation, which leads to the accumulation of ROS (Son et al, 2013;Abrego et al, 2017).…”

“…The 6-ME-induced cytotoxicity was also mitigated by the presence of ZVAD, based on the viability data of OC cells treated with 6-ME alone or in combination with ZVAD (Figure 2F; Supplementary Figure S1C). Based on these results, we conclude that 6-ME triggers OC cell apoptosis, which is a different mode of cell death from the one previously reported in the 6-ME-induced pyroptosis of pancreatic cancer (Ma et al, 2022).…”

“…Our subsequent studies further proved that the addition of OAA significantly impeded 6-MEinduced ROS accumulation (Figure 6C), JNK/MAPK and ERK/ MAPK activation (Figures 6E, F), and increased apoptosis in OC cells (Figures 6G, H). Importantly, 6-ME has been reported that has the potential to bind to the regulatory center of enzymatic activity of PCB, which has been demonstrated to be the key enzyme supplying OAA to the TCA cycle (Ma et al, 2022). Meanwhile, we did not observe changes in PCB expression in 6-ME-treated OC cells by western blot (Figure 5B), suggesting that 6-ME may bind to PCB and then inhibit its activity rather than expression.…”

“…The promising antitumor properties of alkaloids and others extracts from M. cordata have been demonstrated in different cancer types (Zhengfu et al, 2012;Guo et al, 2014;Almeida et al, 2017;Si et al, 2019;Zhu et al, 2019;Ali et al, 2021;Sai et al, 2021). Notably, Frontiers in Pharmacology frontiersin.org our recent study has confirmed that 6-ME can induce mitochondrial dysfunction and ROS/RIPK1-dependent pyroptosis that hinder pancreatic cancer progression (Ma et al, 2022). However, it remains unclear whether 6-ME possess a potential against OC and what the underlying mechanisms of its action might be.…”

Oxaloacetate acid ameliorates paraquat-induced acute lung injury by alleviating oxidative stress and mitochondrial dysfunction

“…However, the role and mechanism of OAA in ALI following PQ exposure remain unclear. Several studies have shown that OAA metabolism is associated with the production of NADPH ( Abrego et al, 2017 ; Ma et al, 2022 ), which can act as a ROS scavenger ( Ito et al, 2021 ), and this may be related to OAA antagonism of oxidative stress caused by PQ. In our study, OAA was found to exert protective effects on PQ-induced lung injury, possibly through inhibited oxidative stress and improved mitochondrial function.…”