Pancreatic ductal adenocarcinoma (PDAC) cells are Gln-metabolism dependence, which can preferentially utilize glutamic oxaloacetate transaminase 1 (GOT1) to maintain the redox homeostasis of cancer cells. Therefore, small molecule inhibitors targeting GOT1 can be used as a new strategy for developing cancer therapies. Here, we identified a cyclobutyrolactone lignan, Aspulvinone H (AH), showing significant GOT1 inhibitory activity in vitro. The complex crystal structure of GOT1-AH elucidated the molecular mechanism, which AH and the cofactor pyrido-aldehyde 5-phosphate (PLP) competitively bound to the active sites of GOT1. Structure-activity relationship (SAR) analysis exhibited that the π-π stacking and isopentenyl side chain of aspulvinone were related to the inhibition of GOT1 activity. Further biological study indicated that AH could suppress glutamine metabolism, which made PDAC cells sensitive to oxidative stress and inhibited cell proliferation. Besides, AH exhibited potent in vivo antitumor activity in the SW1990 cell-induced xenograft model. These findings suggest that AH could be considered as a promising lead molecule for the development of PDAC anticancer agents.
Background and Purpose: We previously found that secoemestrin C, an epitetrathiodioxopiperazine isolated from Aspergillus nidulans, has a potent immunosuppressive effect on splenocyte proliferation in drug screening. Here, we determined the immunomodulatory and hepatoprotective effects of secoemestrin C in a mouse model of acute autoimmune hepatitis. Experimental Approach: In an in vitro assay, purified hepatic mononuclear cells (MNCs) from C57BL/6J mice were stimulated with concanavalin A (Con A, 2 μg·mL-1) in the presence of secoemestrin C, and cell proliferation and cytokine production were measured. In an in vivo assay, mice with or without secoemestrin C pretreatment were injected with Con A (12 mg·kg-1) to induce acute hepatitis. Blood samples and liver tissues were harvested 8 h after Con A injection. Liver injury, serum levels of proinflammatory cytokines, hepatic lymphocyte subset ratios, and the functional status of NKT and conventional T cells were analyzed. Key Results: Secoemestrin C treatment dose-dependently suppressed cell proliferation and proinflammatory cytokine secretion in Con A-stimulated hepatic MNCs in vitro. In Con A-challenged mice, pre-injection with secoemestrin C significantly decreased the generation of proinflammatory cytokines and ameliorated liver injury. Furthermore, pretreatment with secoemestrin C significantly inhibited the Con A-induced activation of NKT and conventional T cells and decreased the production of IFN-γ by these two cell populations. Conclusion and Implications: Secoemestrin C has an immunosuppressive effect on NKT and conventional T cells and has hepatoprotective activity in mouse autoimmune hepatitis. These findings provide new insights into the use of fungus-derived natural products for the treatment of autoimmune diseases.