An anticancer compound becomes more soluble and selective to cancer cells after attaching a glucose group to it
![The active substances from the Glutriptolides family are capable of being used as targeted "cruise missiles" against cancer cells. The glucose part is directed to the glucose carrier (red) anchored to the cell membrane, while directing the toxic triptolide into the cell. [Courtesy: Johns Hopkins University School of Medicine]](https://www.hayadan.org.il/images/content3/2016/11/chinese-medicine-500x402.jpg)
Over twenty years ago, a bulletin board in China piqued the curiosity of a biochemist - where it advertised an extract from a plant known as the "thunder god vine" as an immunosuppressant.
A concise review of published research reveals that the key substance in the extract - the small molecule called triptolide - was discovered twenty years before the advertisement was pasted on the board, and that this substance is able to prevent cell replication. Now, the same biochemist and his colleagues from the Johns Hopkins University School of Medicine report that experiments with this substance in human cells and mouse cells showed improved results thanks to the chemical connection of glucose to the triptolide molecule.
The chemical addition makes the molecule more soluble in water, thus a sort of "cruise missile" that selectively locates cancer cells, according to the researchers. The supplement may also reduce the negative side effects in patients and make it easier to take the medicine. The research findings have long been published in the scientific journal Angewandte Chemie.
"We still have a long way to go before we can test this derivative in humans, but we believe that further adaptations may improve it even more," said Jun O. Liu, professor of pharmacology and molecular sciences at the university's cancer research center, "but already it includes The properties we were looking for: it is quite soluble in water and it focuses on cancer cells more than healthy cells." The professor, who was born in a small town north of Shanghai in China, explains that the plant has been used in traditional Chinese medicine for over four centuries, usually to calm an overactive immune system, a situation that can cause the outbreak of diseases such as arthritis and multiple sclerosis.
The expertise of Professor Jun O. Liu's laboratory is to decipher how natural compounds with known healing properties give rise to their effects on human cells. Five years ago, he and his colleagues discovered that triptolide prevents cell growth by interfering with the XPB protein, part of the transcription factor of the large protein machine called IIH, which in turn is required by the coupling enzyme RNA polymerase II in order to create messenger RNA (mRNA). Due to the fact that the substance prevents the growth of cells, it works well in the fight against the replication phase of cancer cells, explains the lead researcher. Unfortunately, the substance - and many of its derivatives - did not work well in patients due to the fact that they do not dissolve properly in water or blood, and in addition - the substance causes many negative side effects because it also destroys healthy cells.
The latest study by the researchers tried to selectively direct the active substance to the cancer cells using the knowledge that most cancer cells produce additional copies of proteins, called glucose transporters. These carriers create channels through the cell membrane that are designed to bring in enough glucose molecules that are used as a kind of fuel required for the accelerated growth. By attaching glucose to the active ingredient, the researchers hope to trick the cancer cells into taking in the cell-killing poison, as has indeed been shown to be a successful mechanism in other anti-cancer drugs. "We are looking for a preparation that we can give intravenously, which will remain stable in the blood and become most effective when it comes into contact with the cancer cells," explains the researcher.
In the first step, the researchers synthesized five derivatives of the active substance. Each of the derivatives was attached to one glucose molecule at the same position, but through a slightly different linker. A preliminary experiment showed that none of the derivatives were able to block the biological activity of the transcription factor. The lead researcher explains that what appears to be negative news is actually a positive result - this finding implies that the drug will only be active from the moment it enters the cells where the addition of glucose is cut off.
When the five derivatives were tested in human kidney cells, the derivative named glutriptolide 2 slowed cell growth much better than the other derivatives and thus became the only derivative that the study continued with. When the researchers evaluated the effects of the active substance on a variety of healthy cells and cancer cells at the same time using the glutriptolide 2 derivative, they discovered that the substance tended to slow down the growth of healthy cells and cancer cells at the same rate, while the derivative was eight times more effective against cancer cells, on average. The research group plans to examine further changes in terms of the biochemical connectors that bind the glucose to triptolide in order to test whether it is possible to further reduce the toxicity to the healthy cells and increase the efficiency and selectivity against the cancer cells.
