Researchers unlock Sweet Annie's cancer-fighting potential

Artemisia annua

Artemisia annua has been revered in traditional Chinese medicine for over 2,000 years, particularly for producing artemisinin—a compound used in malaria treatment. UTSA's pioneering research aims to delve deeper into the plant’s bioactive properties, specifically focusing on a compound known as Arteannuin B and its potential efficacy in treating cancer and COVID-19.

Sponsel indicates that natural products are invaluable to medical research, with roughly half of all prescription medications originating from them. He also notes that due to the complexity of cancer, it is improbable that a universal treatment will be developed. Therefore, the ongoing investigation into a variety of medicinal substances from various plants remains important.

Interdisciplinary research

The interdisciplinary nature of the research, bridging biochemistry, chemistry, and biology, allows for a nuanced understanding of the medicinal compounds. Lin, an associate professor in the UTSA Department of Integrative Biology and the Department of Neurosciences, Developmental and Regenerative Biology, notes, "We're in the nascent stages of understanding how to best administer these compounds for targeted therapy. The goal is to reduce concentration levels to directly target affected areas."

The team's groundbreaking work has received backing from Mitchel S. Berger, director of the University of California San Francisco (UCSF) Brain Tumor Center, providing glioblastoma cells for study. The findings have been published in the Journal of Natural Products.

Francis K. Yoshimoto, a UTSA assistant professor in chemistry, explains the extraction process: "We utilized methanol as the solvent. This crucial step led us to hypothesize how the compound interacts within biological systems."

As part of the team, doctoral student Kaitlyn Varela carried out fractionation and characterization of the Sweet Annie extracts, employing NMR spectroscopy and liquid chromatography-mass spectrometry. The team tested these fractions against glioblastoma (GBM) cells, a particularly malignant form of brain cancer. Arteannuin B consistently demonstrated toxic activity against these cancer cells.

The researchers believe that Arteannuin B may inhibit cysteine proteases—protein-degrading enzymes—that are overexpressed in cancer cells. "We discovered that when we chemically reduced Arteannuin B, its effectiveness against GBM decreased significantly. This provided critical insights into its bioactive properties," adds Yoshimoto.

Furthering their discoveries, Varela showed that Arteannuin B also hinders the activity of the SARS-CoV-2 main protease and caspase-8, both of which are types of cysteine proteases.

The work of these UTSA researchers brings forth the importance of understanding the biochemical mechanisms at play in medicinal compounds. Yoshimoto sums it up: "To make medicine truly effective, understanding the genetic landscape of diseases like cancer is vital. Knowing what genes are overexpressed can help us target and block the activity of specific protein products, making treatment more effective."

The study is a stellar example of how an interdisciplinary approach can unlock the potential of natural compounds, giving new hope in the fight against diseases that continue to elude complete medical understanding.

The study was published in Journal of Natural Products (2023)

Study Abstract:

Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SARS-CoV-2. In this study, a methyl ester derivative of arteannuin B was isolated when A. annua leaves were extracted with a 1:1 mixture of methanol and dichloromethane. This methyl ester was thought to be formed from the reaction between arteannuin B and the extracting solvent, which was supported by the fact that arteannuin B underwent 1,2-addition when it was dissolved in deuteromethanol. In contrast, in the presence of N-acetylcysteine methyl ester, a 1,4-addition (thiol-Michael reaction) occurred. Arteannuin B hindered the activity of the SARS CoV-2 main protease (nonstructural protein 5, NSP5), a cysteine protease, through time-dependent inhibition. The active site cysteine residue of NSP5 (cysteine-145) formed a covalent bond with arteannuin B as determined by mass spectrometry. In order to determine whether cysteine adduction by arteannuin B can inhibit the development of cancer cells, similar experiments were performed with caspase-8, the cysteine protease enzyme overexpressed in glioblastoma. Time-dependent inhibition and cysteine adduction assays suggested arteannuin B inhibits caspase-8 and adducts to the active site cysteine residue (cysteine-360), respectively. Overall, these results enhance our understanding of how A. annua possesses antiviral and cytotoxic activities.