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Updated: Mar 16, 2026
A Customizable Approach for the Enzymatic Production and Purification of Diterpenoid Natural Products
Published on: October 4, 2019
Boesenberols, Pimarane Diterpenes with TRAIL-Resistance-Overcoming Activity from Boesenbergia pandurata
Utpal K Karmakar1,2, Naoki Ishikawa1, Midori A Arai1
1Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Abstract:
TRAIL is a potent and selective inducer of apoptosis in most cancer cells while sparing normal cells, which makes it an attractive target for the development of new cancer therapies. In a screening program on natural resources with the ability to abrogate TRAIL resistance, the bioassay-guided fractionation of Boesenbergia pandurata rhizomes resulted in the isolation of 17 pimarane diterpenes and a monoterpene. Among these, compounds 1-8, named boesenberols A-H, are new pimarane diterpenes. All compounds exhibited TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells. Subtoxic doses of the major compound 9 sensitized AGS cells to TRAIL-induced apoptosis by up-regulating apoptosis-inducing proteins, such as DR4, DR5, p53, Fas, CHOP, Bak, and cleaved caspases-3, -8, and -9, and down-regulating the levels of cell survival proteins, such as Bcl-2, c-FLIP, and GSK-3β, in TRAIL-resistant AGS cells. Furthermore, compound 9 did not decrease the viability of noncancerous (HEK293) cells at concentrations up to 30 μM.
Insights
Researchers identified natural compounds that overcome cancer cell resistance to TRAIL-induced apoptosis. Compound 9 from Boesenbergia pandurata sensitized resistant cancer cells, offering a potential new therapeutic strategy.
Area of Science:
- Natural Product Chemistry
- Cancer Biology
- Pharmacology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells but not normal cells, making it a promising cancer therapy target.
- Acquired or intrinsic resistance to TRAIL limits its clinical efficacy, necessitating strategies to overcome this resistance.
Purpose of the Study:
- To identify natural compounds capable of abrogating TRAIL resistance in cancer cells.
- To investigate the mechanism by which isolated compounds overcome TRAIL resistance.
Main Methods:
- Bioassay-guided fractionation of Boesenbergia pandurata rhizomes.
- Isolation and structural elucidation of pimarane diterpenes and a monoterpene.
- Assessment of TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells.
- Analysis of apoptosis-related protein expression in response to compound treatment.
Main Results:
- Seventeen pimarane diterpenes and one monoterpene were isolated, including eight new compounds (boesenberols A-H).
- All isolated compounds demonstrated activity in overcoming TRAIL resistance in AGS cells.
- Compound 9 significantly sensitized TRAIL-resistant AGS cells to apoptosis by modulating key proteins in apoptotic and survival pathways.
- Compound 9 exhibited no cytotoxicity in noncancerous HEK293 cells at effective concentrations.
Conclusions:
- Boesenbergia pandurata is a valuable source of compounds that can overcome TRAIL resistance.
- Compound 9 represents a promising lead for developing novel cancer therapeutics that restore TRAIL sensitivity.
- The mechanism involves the upregulation of pro-apoptotic proteins and downregulation of survival proteins, enhancing TRAIL-induced apoptosis without harming normal cells.
