Plant fungus provides new drug with a new cellular target
Novel chemical compounds from a fungus could provide new
perspectives for treating colorectal cancer, one of the most common and
deadliest cancers worldwide. In the journal Angewandte Chemie,
researchers have reported on the isolation and characterization of a
previously unknown class of metabolites (terpene-nonadride
heterodimers). One of these compounds effectively kills colorectal
cancer cells by attacking the enzyme DCTPP1, which thus may serve as a
potential biomarker for colorectal cancer and a therapeutic target.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Rather than using conventional cytostatic
drugs, which have many side effects, modern cancer treatment
frequently involves targeted tumor therapies directed at specific target
molecules in the tumor cells. However, the prognosis for colorectal
cancer patients remains grim—there is a need for new targets and novel
drugs.
Targeted tumor therapies are mostly based on small
molecules from plants, fungi, bacteria, and marine organisms. About half
of current cancer medications were developed from natural substances. A team led
by Ninghua Tan, Yi Ma, and Zhe Wang at the China Pharmaceutical
University (Nanjing, China) chose to use Bipolaris victoriae S27,
a fungus that lives on plants, as the starting point in their search for
new drugs.
The team first analyzed metabolic products by cultivating
the fungus under many different conditions (OSMAC method, one strain,
many compounds). They discovered twelve unusual chemical structures
belonging to a previously unknown class of compounds: terpene-nonadride
heterodimers, molecules made from one terpene and one nonadride unit.
Widely found in nature, terpenes are a large group of compounds with
very varied carbon frameworks based on isoprene units. Nonadrides are
nine-membered carbon rings with maleic anhydride groups. The monomers
making up this class of dimers termed “bipoterprides” were also
identified and were found to contain additional structural novelties
(bicyclic 5/6-nonadrides with carbon rearrangements).
Nine of the bipoterprides were effective against colorectal
cancer cells. The most effective was bipoterpride No. 2, which killed
tumor cells as effectively as the classic cytostatic drug Cisplatin. In
mouse models, it caused tumors to shrink with no toxic side effects.
The team used a variety of methods to analyze the drug’s
mechanism: bipoterpride 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an
enzyme that regulates the cellular nucleotide pool. The heterodimer
binds significantly more tightly than each of its individual monomers.
The activity of DCTPP1 is elevated in certain types of tumors, promoting
the invasion, migration, and proliferation of the cancer cells while
also inhibiting programmed cell death. It can also help cancer cells to
resist treatment. Bipoterpride 2 inhibits this enzymatic activity and
disrupts the—pathologically altered—amino acid metabolism in the tumor
cells.
The team was thus able to identify DCTPP1 as a new target
for the treatment of colorectal cancer and bipoterprides as new
potential drug candidates.
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About the Author
Dr Zhe Wang is an Associate Professor at School of Traditional Chinese
Pharmacy, China Pharmaceutical University, whose research field lies on
Natural Medicinal Chemistry and Tumor Pharmacology. He is interested in
the discovery of bioactive products from Chinese medicinal plants and
their endophytic fungi, target identification and action mechanism.
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