Research published in Angewandte Chemie reveals that novel chemical compounds derived from a fungus could provide fresh avenues for treating colorectal cancer, a leading cause of cancer-related deaths worldwide.
Scientists have successfully isolated and characterized a new class of metabolites called terpene-nonadride heterodimers. One of these compounds has shown the ability to kill colorectal cancer cells by targeting the enzyme DCTPP1, which may serve as both a potential biomarker and a therapeutic target for the disease.
Unlike conventional chemotherapy drugs that often come with significant side effects, modern cancer treatment increasingly relies on targeted therapies aimed at specific molecules within tumor cells. Despite these advancements, the prognosis for patients with colorectal cancer remains poor, underscoring the urgent need for new treatment options.
Current targeted therapies primarily utilize small molecules sourced from plants, fungi, bacteria, and marine organisms, with about half of existing cancer medications derived from natural substances.
A research team led by Ninghua Tan, Yi Ma, and Zhe Wang from China Pharmaceutical University in Nanjing focused on the fungus Bipolaris victoriae S27, which typically inhabits plants, to discover new drug candidates.
To identify potential compounds, the researchers cultivated the fungus under various conditions using the OSMAC method, which allows for the exploration of many compounds from a single strain. This approach led to the discovery of 12 unique chemical structures classified as terpene-nonadride heterodimers, composed of one terpene and one nonadride unit.
Terpenes are widely found in nature and are characterized by diverse carbon frameworks based on isoprene units. Nonadrides are nine-membered carbon rings containing maleic anhydride groups.
The researchers also identified monomers within this new class, termed “bipoterprides,” which showcased additional structural features, including bicyclic 5/6-nonadrides with unique carbon arrangements.
Of the bipoterprides identified, nine exhibited effectiveness against colorectal cancer cells. The standout compound, bipoterpride No. 2, demonstrated cancer-killing abilities comparable to the well-known chemotherapy drug Cisplatin. In mouse models, bipoterpride No. 2 led to tumor shrinkage without causing toxic side effects.
The team conducted various analyses to understand the drug’s mechanism of action. They found that bipoterpride No. 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an enzyme that plays a critical role in regulating the cellular nucleotide pool.
Notably, this heterodimer binds more tightly to DCTPP1 than either of its individual components. Elevated levels of DCTPP1 in certain tumor types promote cancer cell invasion, migration, and proliferation while hindering programmed cell death. This enzyme can also enhance cancer cells’ resistance to treatment.
By inhibiting DCTPP1’s activity, bipoterpride No. 2 disrupts the altered amino acid metabolism in tumor cells, marking DCTPP1 as a promising new target for colorectal cancer treatment and bipoterprides as potential drug candidates.
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