Novel chemical compounds derived from a fungus may offer fresh insights into the treatment of colorectal cancer, which ranks among the most prevalent and lethal cancers globally. Researchers have unveiled the isolation and examination of a previously unidentified class of metabolites known as terpene-nonadride heterodimers. Notably, one of these compounds demonstrates the ability to effectively eradicate colorectal cancer cells by targeting the enzyme DCTPP1. This discovery suggests that DCTPP1 might be used as both a potential biomarker for colorectal cancer and a target for therapy.
Newly discovered chemical compounds sourced from a type of fungus could lead to innovative approaches to combating colorectal cancer, a leading cause of cancer-related deaths worldwide. A report in the journal Angewandte Chemie details researchers’ efforts to isolate and characterize a new class of metabolites termed terpene-nonadride heterodimers. Among these compounds, one has shown remarkable effectiveness in killing colorectal cancer cells by inhibiting the enzyme DCTPP1, presenting this enzyme as a possible biomarker and therapeutic target for colorectal cancer.
Modern cancer therapies increasingly favor targeted treatments over traditional cytostatic drugs, which often come with various side effects. Unfortunately, the outlook for those with colorectal cancer remains poor, highlighting the urgent need for new therapeutic targets and innovative drugs.
Targeted therapies primarily utilize small molecules derived from natural sources such as plants, fungi, bacteria, and marine life. Around fifty percent of current cancer treatments are based on natural compounds. A research group led by Ninghua Tan, Yi Ma, and Zhe Wang from China Pharmaceutical University in Nanjing decided to explore Bipolaris victoriae S27, a plant-associated fungus, to discover new treatment options.
The researchers began by investigating the metabolic byproducts of the fungus under varied growth conditions using the OSMAC method (one strain, many compounds). This led to the discovery of twelve unique chemical structures classified within the newly identified terpene-nonadride heterodimers. These molecules consist of both a terpene unit and a nonadride component. Terpenes, found abundantly in nature, are diverse compounds built from isoprene units, while nonadrides are characterized by nine-membered carbon rings featuring maleic anhydride groups. Additional structural innovations were found in the monomers of this dimer class known as “bipoterprides,” including bicyclic 5/6-nonadrides with rearranged carbon structures.
Nine of the bipoterprides exhibited anti-cancer activity. The most potent among them, bipoterpride No. 2, was capable of killing tumor cells as effectively as the traditional cytostatic agent Cisplatin. In tests using mouse models, it induced tumor shrinkage without causing toxic side effects.
To better understand the compound’s mechanism of action, the research team utilized various analytical techniques: bipoterpride 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an enzyme critical in regulating the cellular pool of nucleotides. The heterodimer displays significantly stronger binding affinity compared to its individual monomer components. Elevated levels of DCTPP1 are associated with specific tumor types, facilitating cancer cell invasion, migration, and growth, while simultaneously suppressing programmed cell death and aiding in treatment resistance. Bipoterpride 2 interrupts this enzymatic function and alters the aberrant amino acid metabolism present in tumor cells.
Consequently, the research team has identified DCTPP1 as a novel target for colorectal cancer treatment and has positioned bipoterprides as promising drug candidates for future research.
