A Spoonful of Sugar Helps the Medicine Fight Cancer

BY GRACIE JIN

Lei gong teng, or the thunder god vine. Source: Wikimedia Commons.

In September, a team of researchers at the Johns Hopkins School of Medicine discovered that the addition of glucose, a simple sugar, could transform a plant extract into a drug with potentially anti-cancer effects. To put it another way, Mary Poppin’s age-old lyric “a spoonful of sugar helps the medicine go down” became, albeit metaphorically, a biomedical reality. The researchers’ findings were published in the German Chemical Society journal Angewandte Chemie, offering a promising bridge between eastern and western medicine.

The story begins in 1993 when Jun Liu, professor of Pharmacology and Molecular Biology at Johns Hopkins, spotted an advertisement while attending a conference in China:

“I walked out of my hotel, and there was this billboard advertising an extract from the thunder god vine as a novel immunosuppressant. I was already working on two immunosuppressive drugs isolated from microbes, so this piqued my interest.”

Thunder god vine has a 400-year history in traditional Chinese medicine and was used to calm overactive immune responses in conditions such as rheumatoid arthritis and multiple sclerosis. Its active ingredient, Triptolide, is not a novel molecule; its mechanism of halting cell growth had been well documented. Five years ago, Liu and colleagues found that triptolide kills cancer cells in vitro by irreversibly inhibiting a protein known as XPB, which is involved in RNA synthesis and DNA repair. However, the molecule’s anti-cancer capability does not extend well beyond the laboratory. Its ineffectiveness in humans is mainly due to two limitations: first, triptolide does not dissolve adequately in water or blood, which makes the drug difficult to administer. Second, the its killing mechanism does not distinguish between healthy cells and tumorous cells, which leads to toxic side effects.

To tackle these limitations and make Triptolide a viable form of chemotherapy, three research groups joined forces across continents—–Liu, from Johns Hopkins, his colleague Pomper (also from JHU), and Yu from the Chinese Academy of Sciences.

“We were looking for something that could be administered intravenously, remain stable in the blood and then become active as soon as it was imported into cancer cells,” says Liu.

The team of scientists started their research with the knowledge that most cancer cells overproduce glucose transporters, which allows the cancerous cells to absorb maximum amounts of glucose to use as energy to reproduce. Liu’s team hypothesized that attaching glucose to triptolide would trick the cancer cells into thinking that the triptolide was actually sugar, causing them to absorb the toxin and die.

To test their theory, the chemists first synthesized five derivatives of triptolide, each with glucose inserted the same spot, but attached with different “linkers.” When these five “glutriptolides” were tested in human embryonic kidney cells, glutriptolide 2 won the race: it reduced the cancer cells’ uncontrolled replication more effectively than all the rest.

The next part of the study was to compare glutriptolide 2 to triptolide, to see if the former was really better at targeting cancerous cells. The researchers found that while triptolide targeted cell growth in both cancer and healthy cells without selectiveness, the glucose-enhanced glutriptolide 2 was 8 times more likely to attack cancer cells vs. healthy cells.

According to Liu, “the new compound is quite water soluble, it prefers cancer cells over healthy cells and could therefore have fewer side effects.”

So, Mary Poppins was right. A spoonful of sugar does help the medicine go down, or at least makes it more effective. But every new drug has risks: how toxic, exactly, is the man-made glutriptolide? Is it safe to digest? Will it destroy healthy human tissue? While these questions require further research, laboratory tests on mice show positive results. Mice can tolerate a dose of glutriptolide 5 times higher than triptolide, all the while eradicating prostate cancer tumors faster and resisting recurrence for 3 weeks. Dr. Liu expressed “[total surprise] to see that sustained antitumor activity.” Exciting research is currently underway to tweak the links between triptolide and glucose to maximize cancer cell-killing and minimize healthy cell-killing.

Billboard advertising the extract of the thunder god vine as an immunosuppressant in China. Source: Johns Hopkins.

Dr. Liu’s company Rapafusyn Pharmaceuticals Incorporated, of which he is a co-founder and board member, has a nondisclosure agreement with Johns Hopkins University regarding their research on triptolide. “Right now, we think of triptolide as the explosives you pack into a missile. It’s too toxic to be let loose,” Dr. Liu explains. The researchers do not want their work with triptolide to be applied in potentially dangerous settings. “So we’re engineering a ‘missile head’ for it,” says Dr. Liu, “to direct it solely to cancer cells. We should know in a few years’ time if it works.”

Dr. Liu is part of an ongoing effort to bring two symbiotic eastern and western systems of medicine closer together. Another scientist with a similar endeavor named Dr. Youyou Tu received the 2015 Nobel Prize in Physiology or Medicine for discovering the malaria drug artemisinin in the extracts of an ancient medicinal plant, Artemisia annua. Yet another leader in traditional Chinese medicine research, Yale professor Dr. Yung-Chi Cheng, is developing a four-herb combination called PHY906 to reduce chemotherapy side effects in colon cancer. Dr. Cheng also serves as chairman of the Consortium for the Globalization of Chinese Medicine, a nonprofit aiming to widen the benefits of Chinese herbal medicine globally.

These scientists’ work shed valuable light on modern global health. As Johns Hopkins history of medicine professor Marta Hanson puts it, researchers like Liu and Tu are “medically bilingual” —fluent in not only two languages, but also the complex nuances of two contrasting worlds of medicine.

While some believe traditional Chinese medicine to be bogus and arcane, Chinese medical therapies are still in demand around the world. They meet the needs of patients who either culturally feel more comfortable with them or are dissatisfied with what Western medicine is able to provide. Hanson describes traditional Chinese medicine as a mirror that reflects both the strengths and shortcomings of western medicine, therefore offering it routes through which to grow. A synergistic integration between holistic approaches and evidence-based treatment would benefit all hemispheres of the globe. Each sweet discovery is a taste of more exciting developments that lie ahead.

Gracie Jin is a freshman in Berkeley College interested in studying neuroscience and global health. She can be contacted at grace.jin@yale.edu.

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References:

1. Consortium for Globalization of Chinese Medicine. (n.d.). Retrieved from http://www.tcmedicine.org/en/default.asp.

2. He, Q., Minn, I., et al. (2016). Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angewandte Chemie, 55(39): 12035-12039. Retrieved from httpp://onlinelibrary.wiley.com/doi/10.1002/anie.201606121/full.

3. Wang, S. S. (2014, November 3). A Push to Back Traditional Chinese Medicine With More Data. The Wall Street Journal. Retrieved from http://www.wsj.com/articles/a-push-to-back-traditional-chinese-medi-cine-with-more-data-1415036616.

4. Gara, C. (n.d.) When East Meets West. Johns Hopkins Medicine. Retrieved from http://www.hopkinsmedicine.org/research/advance-ments-in-research/fundamentals/in-depth/when-east-meets-west.

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