New chemical compounds from fungi may provide latest approaches to the treatment of colorectal cancer, one of the crucial common and deadliest cancers worldwide. In the journal, researchers report the isolation and characterization of a previously unknown class of metabolites (terpene-nonahydride heterodimers). One of those compounds effectively kills colon cancer cells by attacking the enzyme DCTPP1, which can thus function a possible biomarker and therapeutic goal for colorectal cancer.
Instead of using traditional cytostatic drugs, which have many negative effects, modern cancer treatments often involve tumor therapies directed at specific goal molecules in tumor cells. However, the prognosis for colorectal cancer patients is grim — latest targets and latest drugs are needed.
Targeted tumor therapies are mostly based on small molecules from plants, fungi, bacteria and marine organisms. About half of the present cancer drugs are derived from natural substances. A team led by Ninghua Tan, Yi Ma, and Zhi Wang at China Pharmaceutical University (Nanjing, China) selected to make use of plant-dwelling fungi as a start line for the search for brand new drugs.
The team first analyzed the metabolic products by cultivating the fungus under several different conditions (the OSMAC method, one strain, several compounds). They discovered twelve unusual chemical structures belonging to a previously unknown class of compounds: terpene-nonanhydride heterodimers, molecules composed of a terpene and a nonanhydride unit. Widely present in nature, terpenes are a big group of compounds with very different carbon frameworks based on isoprene units. Nonadrides are nine-membered carbon rings with maleic anhydride groups. Monomers forming a category of dimers called “bipoterprides” were also identified and extra structural novelties were found (bicyclic 5/6-nonanhydrides with carbon rearrangement).
Nine of the bipeptides were effective against colorectal cancer cells. The only was bibutterpide number 2, which killed tumor cells as effectively because the classic cytostatic drug cisplatin. In mouse models, it caused tumors to shrink with none toxic negative effects.
The team used different methods to investigate the drug's mechanism of motion: Bipoterpride 2 inhibits DCTP-pyrophosphatase 1 (DCTPP1), an enzyme that regulates the cellular nucleotide pool. The heterodimer binds significantly more strongly than each of its individual monomers. DCTPP1 activity is elevated in certain kinds of tumors, promoting cancer cell invasion, migration, and proliferation while also inhibiting programmed cell death. It can also help cancer cells resist treatment. Bipoterpride 2 inhibits this enzymatic activity and inhibits the — pathologically altered — amino acid metabolism in tumor cells.
The team was thus capable of discover DCTPP1 as a brand new goal for the treatment of colorectal cancer and bipoteramides as latest drug candidates.