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Could a Malaria Drug Treat Cancer One Day?

The Artemisia annua plant, or "Sweet Annie".
The plant is Artemisia annua, or Sweet Annie, and it contains medicinal compounds. UTSA researchers are studying the plant to understand the bioactive properties of one of these compounds, Arteannuin B, in cancer cells and COVID, the disease caused by the virus, SARS-CoV-2. Credit: The University of Texas at San Antonio.
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While researching a cure for malaria, researchers discovered and characterized several bioactive compounds from the plant Artemisia annua (A. annua), or “Sweet Annie”. The Nobel Prize-winning effort saved millions of lives and might pave the way for novel cancer therapies. But there’s a roadblock – scientists aren’t clear on how the compounds work.

The discovery of artemisinins

During the Vietnam War, a particularly deadly strain of malaria caused a large number of fatalities among soldiers due to its resistance to the antimalarial drug chloroquine. Scientists in China were tasked with helping the north Vietnamese find a cure, resulting in the construction of an official task force – Project 523 – in 1967.

A few years after its launch, Chinese scientist Tu Youyou was appointed as head of Project 523. She traveled to Hainan Island in southern China – where a chloroquine-resistant outbreak was ongoing – and witnessed the devastation of the disease firsthand. After returning to Beijing, Youyou questioned whether traditional Chinese medicine could offer inspiration in the quest for a cure. Over 240,000 compounds had been tested as antimalarial drugs by that point, none of which had proven effective.

While studying ancient texts and conducting research with practitioners, Youyou’s team came across over 2,000 traditional Chinese recipes, and tested a variety of extracts in the lab for their antimalarial properties. They discovered that sweet wormwood (A. annua) had been used to treat fevers in traditional Chinese medicine for thousands of years. The plant produces a compound called artemisinin, which – after several attempts at refining the preparation and extraction process – Youyou was able to obtain in its pure form. She tested artemisinin on mice and monkeys before bravely volunteering herself as the first human subject. It was found to be incredibly effective at treating malaria, and in 1981, Youyou presented her findings to the World Health Organization (WHO). It would take several decades, but the organization eventually recommended artemisinin combination therapy, or ACT, as the first line of defense against malaria, earning Youyou the 2015 Nobel Prize in Physiology or Medicine. The discovery of artemisinin has been hailed as “arguably the most important pharmaceutical intervention in the last half-century”.


Artemisinins are a family of anti-malarial agents that are derived from A. annua, including but not limited to artesunate, artemether and arteether. Dihydroartemisinin is the active metabolite of all artemisinin compounds, which is also used as a drug itself.

Artemisinin’s promise hindered by lack of MOA

Since Youyou’s groundbreaking work, A. annua and its compounds have been studied for biotherapeutic applications beyond malaria treatment, most notably in cancer research. Artesunate, a semi-synthetic derivative, was screened against 55 cancer cell lines in 2001, where it was found to be most effective against leukemia and colon cancer. Over the last decade, a number of human clinical trials have utilized the compound against cancers including small lung cell cancer, cervical cancer and breast cancer, with encouraging results.

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Drug repurposing became a major research focus during the COVID-19 pandemic. This approach carries several benefits over developing drugs de novo; the safety of authorized drugs is known, which can help to fast-track the laborious and often costly process of bringing new drugs to market. Previous research had shown artemisinin demonstrates activity against coronaviruses, which led some to hypothesize that it could be a potential broad-spectrum antiviral drug. Several studies analyzed the efficacy of the drug against SARS-CoV-2 through in vitro and in silico studies.

While some public figures notoriously pushed artemisinin-containing “tonics” in the form of brewed teas or coffees, the use of nonpharmaceutical artemisinin was ultimately discouraged by public health authorities during the pandemic. In 2020, the WHO published a release addressing its position on the use of the plant for COVID-19 prevention or treatment, stating “available in vitro data suggests that purified artemisinin compounds or A. annua plant product or extracts do not have an appreciable effect against COVID-19 at concentrations that could be safely achieved in humans.” Suboptimal dosing of artemisinin compounds can contribute to artemisinin partial resistance, a continuously growing problem in various parts of the world that impacts our ability to fight against malaria. Members of the science community also voiced concerns that, alongside insufficient evidence demonstrating artemisinin’s effectiveness against SARS-CoV-2, its mechanism of action (MOA) was not clear.

This has been a key bottleneck in the development of A. annua bioactives as pharmaceuticals; while they demonstrate efficacy against several human diseases, our understanding of how they exert such benefits is murky.

Over at the University of Texas at San Antonio (UTSA), an interdisciplinary team including Professor of Biology Valerie Sponsel, Assistant Professor of Chemistry Francis Yoshimoto and Associate Professor Annie Lin have been growing and studying A. annua plants to try and find answers.

Arteannuin B inhibits protease activity

In a study published in Natural Products, the researchers worked in collaboration with Dr. Mitchel S. Berger, professor and director of the University of California San Francisco (UCSF) Brain Tumor Center, to extract the natural product arteannuin B from A. annua using methanol, testing its cytotoxic activity in glioblastoma (GBM) cells. “We used methanol as the solvent to extract the compound, and that’s where I got the idea that this must be how it works in biological systems,” says Yoshimoto.

What is glioblastoma?

Glioblastoma is an aggressive and currently incurable form of brain cancer.

The reaction between arteannuin B and methanol produced a methyl ester derivative of arteannuin B, which consistently showed cytotoxic activity against the GBM cells. The team propose that the compound might inhibit cysteine proteases, which are overexpressed in cancer cells and facilitate their growth.

“We then derivatized arteannuin B by chemically reducing it, and Dr. Lin showed that the reduced form of arteannuin B was not active against GBM at the same concentration. This result informed us how arteannuin B has bioactive properties,” Yoshimoto says. “To expand on our results, Kaitlyn [Kaitlyn Varela, a postdoctoral student in Yoshimoto’s laboratory and first author of the paper] showed that arteannuin B hinders the activity of SARS-CoV-2 main protease and caspase-8. Both enzymes are cysteine proteases.”

Developing targeted cancer therapies using artemisinins

While the team are in the early phases of deciphering the bioactive potential of A. annua extracts, they hope that this knowledge could eventually generate targeted cancer therapies. “All of our bodies are different. Cancer, for example, overexpresses certain genes and if you know what gene is being expressed then you can target it and block the activity of its protein product with a drug. One specific example is with tamoxifen, which is a prodrug that is metabolized to its active form, endoxifen, by a key enzyme in the body, cytochrome P450 2D6,” says Yoshimoto.

“Endoxifen blocks the activity of the estrogen receptor, which some estrogen-dependent breast cancers overexpress and need to grow,” he continues. Some people carry more or less active forms of the P450 2D6 enzyme, which impacts the effectiveness of tamoxifen. “To be able to understand the mechanism of how medicines work is really powerful because it enables medication to be given more effectively,” Yoshimoto adds.

Plant-derived bioactives, administered directly, as adjuvants or in combination with other therapies, may also help clinicians in overcoming issues associated with current therapies, such as toxicity and treatment resistance. “As far as cancer is concerned, there are several types of compounds that have always existed but have only been discovered in the last half century,” says Sponsel. “There’s never going to be one compound that treats all cancers, so that is why research continues,” she adds.

As for artemisinin, in Pharmacology and Therapy, Augustin et al emphasize that an artemisinin drug repurposing program, tested in several different cancer types and in a number of different clinical settings, is “urgently needed.”