Chemical Constituents with GNMT-Promoter-Enhancing and NRF2-Reduction Activities from Taiwan Agarwood Excoecaria formosana

Abstract

Hepatocellular carcinoma (HCC) is considered to be a silent killer, and was the fourth leading global cause of cancer deaths in 2018. For now, sorafenib is the only approved drug for advanced HCC treatment. The introduction of additional chemopreventive agents and/or adjuvant therapies may be helpful for the treatment of HCC. After screening 3000 methanolic extracts from the Formosan plant extract bank, Excoecaria formosana showed glycine N-methyltransferase (GNMT)-promoter-enhancing and nuclear factor erythroid 2-related factor 2 (NRF2)-suppressing activities. Further, the investigation of the whole plant of E. formosana led to the isolation of a new steroid, 7α-hydroperoxysitosterol-3-O-β-d-(6-O-palmitoyl)glucopyranoside (1); two new coumarinolignans, excoecoumarin A (2) and excoecoumarin B (3); a new diterpene, excoeterpenol A (4); and 40 known compounds (5–44). Among them, Compounds 38 and 40–44 at a 100 μM concentration showed a 2.97 ± 0.27-, 3.17 ± 1.03-, 2.73 ± 0.23-, 2.63 ± 0.14-, 6.57 ± 0.13-, and 2.62 ± 0.05-fold increase in GNMT promoter activity, respectively. In addition, Compounds 40 and 43 could reduce NRF2 activity, a transcription factor associated with drug resistance, in Huh7 cells with relative activity of 33.1 ± 0.2% and 45.2 ± 2.5%. These results provided the basis for the utilization of Taiwan agarwood for the development of anti-HCC agents.

Coumarinolignans with Reactive Oxygen Species (ROS) and NF-κB Inhibitory Activities from the Roots of Waltheria indica

“…The UV, IR and 1D NMR spectroscopic data of 5 were very close to those of durantin C ( 6 ) [ 22 ], which was purified from same subfraction by HPLC. Fortunately, there existed a pattern that C-7 (δ C 137.4 in 6 vs. 136.8 in 5 ) was shifted to high field and C-8 (δ C 132.1 in 6 vs. 132.7 in 5 ) shifted to low field when the connection mode converted from C-7–O–C-7′ to C-7–O–C-8′ [ 23 , 24 ]. In view of these similarities, 5 was logically assumed to be the regioisomer of 6 , which was further verified by the HMBC couplings between C-8 and H-7′ (δ H 4.91), and between C-7 and H-9′ (δ H 4.07) ( Figure 2 ).…”

An Overview of the Genomic Characterization of Hepatocellular Carcinoma

“…70 Interestingly, a recent drug screening study showed that NRF2 activity is potentially regulated by the oncosuppressor GNMT. 71 Taken together, these observations show that NRF2 is a main regulator of the antioxidative and detoxification responses and propels the progression of cancer, formation of metastases, and resistance to therapy. 72 In addition to mutations in cancer-related genes, HCC tumors harbor mutations in serum proteins such as albumin (ALB) and apolipoprotein B (APOB), which are not frequently mutated in other cancer types.…”

“… 70 Interestingly, a recent drug screening study showed that NRF2 activity is potentially regulated by the oncosuppressor GNMT. 71 Taken together, these observations show that NRF2 is a main regulator of the antioxidative and detoxification responses and propels the progression of cancer, formation of metastases, and resistance to therapy. 72 …”

Identification of Beilschmiedia tsangii Root Extract as a Liver Cancer Cell–Normal Keratinocyte Dual-Selective NRF2 Regulator

“…Luciferase reporter assay and cell viability assay were performed based on methods described in a previous paper [ 22 ]. Relative luciferase activity (RLA) was calculated by normalizing luciferase activity to cell viability.…”