Anti-cancer drugs are some of the most expensive and sought-after medications on the planet. Existing chemotherapies are quite potent, but they effect both healthy and cancerous cells, leading to debilitating side-effects. Furthermore, cancerous cells that survive chemo treatments can develop a resistance to the drug being used. Even worse, some types of chemotherapy can even cause new cancers to form. For these reasons, there is a need to develop a wider array of chemo drugs that are more effective while doing less harm to patients.
Cannabinoids and their derivatives have been gaining attention in recent years as potential anti-cancer agents. For example, a paper released in 2007 compared a cannabinoid derivative called HU-331 to doxorubicin, a widely-prescribed chemotherapy drug. Both compounds are classified as topoisomerase type-II (TOP2) blockers. The massive DNA strands found within cells often get tangled up, leading to potential damage. TOP2 enzymes relieve these tangles by cutting the DNA, passing a neighboring strand through the hole, then repairing the cut. Without TOP2 enzymes, cells are unable to grow and divide properly, eventually dying. TOP2 blockers have the strongest effect on actively growing cells, like those in a cancerous tumor, making them potent chemotherapy drugs. The authors of this paper showed that HU-331 was more effective and less toxic than doxorubicin. However, this pre-clinical data has yet to spur clinical trials in the US.
Now, a separate group has published published new data regarding the mechanism of action of HU-331, and a potential new cannabinoid-based source of chemotherapy called oxidized CBD. Furthermore, they investigate the ability of unaltered CBD to exert an effect on TOP2 enzymes. Finally, they looked at the ability of these compounds to affect two different types of TOP2, both of which are found in humans.
This work was partly motivated by previous research on the synthesis of HU-331. Certain sites on the CBD molecule are modified to form HU-331, through a process known as oxidation. However, there are many other sites that are amenable to the same modifications, which may produce medically useful compounds. Therefore, the first thing the researchers did was to develop a method to oxidize CBD. Using a number of analytical tools, they demonstrated that their method generated a mixture of various oxidized CBD molecules. This oxidized CBD mixture was used in their later experiments.
Next, they tested the ability of oxidized CBD to inhibit TOP2 enzymes. This involves mixing pieces of tangled, or “supercoiled”, DNA in a test tube with TOP2 enzymes, and then adding the various compounds under study to determine whether or not TOP2 is still functional. As positive controls, they used HU-331 and etoposide, a known TOP2 blocker, and demonstrated that their experiment worked as expected. Then, they repeated the experiment using either oxidized or unaltered CBD. The oxidized CBD mixture was able to inhibit TOP2 function, while unaltered CBD did not.
The next task was to determine whether or not oxidized CBD is a TOP2 “poison” or “inhibitor”. The difference is that poisons leave behind breaks in the DNA, while inhibitors do not. To test this, they used an experiment designed to detect breaks in the DNA molecule, comparing oxidized CBD to known poisons and inhibitors. They found that oxidized CBD acts as an inhibitor, resulting in fewer DNA breaks than the poison. Further experiments showed that the TOP2 enzyme consumed less molecular fuel when exposed to oxidized CBD or HU-331, and that these compounds lock the “clamp” portion of TOP2 closed, keeping it from interacting with DNA. These experiments demonstrate that oxidized CBD, like HU-331, is a TOP2 inhibitor.
There are several key take-aways from this article. First and foremost, it reinforces the idea that cannabinoids and their derivatives are a viable source of medically relevant molecules. Further, the finding that oxidized CBD is an inhibitor, rather than a poison, is particularly interesting, since TOP2 poisons can be carcinogenic. TOP2 inhibitors still damage growing cells, but do not leave behind breaks in the DNA, making them potentially safer. Finally, the authors found that oxidized CBD and HU-331 inhibit two forms of TOP2, labeled A and B. The fact that these compounds effect multiple targets makes it less likely that a cancer could develop resistance to these drugs.
This article is not without its limitations. For example, many of the observed effects of HU-331 and oxidized CBD are quite mild, even when used at high concentrations. This may preclude their use as cancer drugs, as doing so could require such high doses that it would be dangerous. It’s also important to remember that oxidized CBD is a mixture of compounds, not a purified drug, so further research will be required to determine which CBD derivative is having these effects. Finally, all of these experiments were performed in test tubes, so it is unclear what effects oxidized CBD will have in living subjects. That said, this is an exciting finding that may point to new, safer chemotherapy drugs derived from the cannabis plant.