Search

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL-resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Upon screening for compounds with B cell-specific Moloney murine leukemia virus region 1 (BMI1) promoter inhibitory activity, 3 nonactic acid derivatives (1-3) were isolated from Streptomyces werraensis IFM12104. Although spectral data of compound 1 were identical with those reported in literature for 4α-(3, 5-dihydroxy-heptyl)-3α-methyl-2-oxetanone (4), compound 1 was revealed to be homononactic acid by X-ray analysis. Compounds 2 and 3 were identified as bishomononactic acid and nonactic acid using spectral data. The 3 compounds 1 to 3 inhibited BMI1 promoter activities with IC50 values of 240, 160, and 180 μM, respectively.

TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.

In the courses of our search for bioactive natural products on TRAIL resistance-overcoming activity, the active EtOAc extract from the bark of Celtis tetrandra was chemically investigated. The fractionation of the extract resulted in the isolation of flavanols; (+)-afzelechin (1), (-)- epiafzelechin (2), (-)-catechin (3), and two new flavanol dimers; (-)- epiafzelechin-(4α→8)-(-)-catechin (4) and (-)- epiafzelechin-(4α→8)-(-)- epicatechin (5). All isolated compounds 1-5 were tested for their TRAIL resistance-overcoming activity against AGS cells at the concentrations from 5–20 μM. It is likely that the flavanol dimers 4 and 5 exhibited weak activity in the range of the concentration of 10–20 μM as compared with the standard.

TRAIL selectively kills cancer cells without harming most normal cells. However, TRAIL resistance is a major problem for its therapeutic use. Developing a strategy to overcome resistance is crucial for the successful use of TRAIL as an antitumor agent. In our screening program of natural products that can abrogate TRAIL resistance, four germacranolides (1–4) were isolated from the aerial parts of Enhydra fluctuans. All compounds exhibited potent TRAIL-resistance overcoming activity against TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids – scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 μM, respectively in TRAIL-resistant AGS cells.