Thapsigargin is a naturally occurring compound found in a plant known as ‘deadly carrots’. After being used for hundreds of years in traditional medicine, it is now being researched as a treatment for cancer and for use as broad spectrum antiviral drug. This article explains the science behind how it works and how researchers are using it to develop drugs with the potential to save millions of lives.
Humans have been using plants in traditional medicine for thousands of years, and in our modern world naturally occurring compounds from plants are a vital source for our pharmaceutical drugs. Traditional medicines might be able to cure a disease however they are not as efficient as drugs for a range of reasons, for example: they may have undesirable side effects, be difficult to absorb or metabolise too fast. Researchers optimise the effects of naturally occurring compounds by modifying their structure to synthesise chemically similar compounds known as analogs.
Thapsigargin is a naturally occurring compound found from a genus of poisonous plants called Thapsia, which are commonly known as ‘deadly carrots’. It is found around the Mediterranean and North Africa and for centuries it has been used in local medicines. Algerians used it as a pain reliever, and others in the area used it to treat lung diseases, rheumatic pain, female infertility, fever and catarrh.
Scientists have been researching its potential as a treatment for cancer and use as a broad spectrum antiviral.
A Promising Cure for Cancer
Thapsigargin is a very potent cytotoxin, a cytotoxin is a chemical which is toxic to cells and leads to apoptosis (cell death). The relative safety of drugs is measured by their therapeutic index (TI), and the larger the TI the safer the drug. Chemically unmodified thapsigargin has no TI, so an effective dose will also produce unacceptable adverse toxic effects. This, combined with the fact that it is poorly water soluble means that researchers prefer to use its analog, known as 12-ADT.
Thapsigargin inhibits SERCA pumps, which are responsible for regulating calcium levels inside cells. This causes calcium ions to build up inside the cells mitochondria, which disrupts normal cell metabolism and leads to apoptosis. Since inhibition of SERCA pumps have previously been used to target solid tumours, it was only natural that researchers started investigating wether thapsigargin or its analogs could be used in cancer treatments.
One of the many hurdles they had to overcome is that thapsigargin is non-specific, meaning it leads to apoptosis in normal cells as well as cancerous cells. This is not an uncommon problem in drug synthesis, and to overcome it researchers use prodrugs. Prodrugs have negligible activity in terms of their intended pharmaceutical actions but once inside the body they are metabolised into the pharmaceutically active drug. The unique properties of cancer cells were used to develop a prodrug delivery system that takes thapsigargin directly to the cancer sites so that it is only activated once inside the tumour.
GenSpera, a biotech company in Texas, made a massive breakthrough when they announced they cured a cancer patient using a prodrug of thapsigargin called mipsagargin, or G202. Previous drugs would stop new blood vessels growing, which would eventually kill off the tumour, however their prodrug delivery system uses G202 to kill the tumour by targeting and killing established blood vessels as well as preventing the growth of new ones.
G202 is currently in a Phase II clinical trial to target HCC (a type of liver cancer) and glioblastoma (one of the most aggressive brain cancers).
A Promising Broad Spectrum Antiviral – Covid-19, Influenza A and RSV
Incredibly thapsigargin has even more pharmaceutical potential, and research is being conducted into its potential as a broad-spectrum antiviral.
Antibiotics, which target bacterial infections, aim to destroy the intended pathogen by targeting certain chemical reactions that take place inside the bacterial cells. However viruses work differently, once inside a host cell they use that cells resources and energy to complete their own life cycle, meaning they do not have their own proteins and enzymes which drugs can specifically target. Most antivirals are specific – they are effective in targeting one type of virus, but not others, in fact the 90 approved antivirals are only effective in treating nine human viral diseases.
These antivirals are virus-centred drugs and focus on ways to target that specific viruses proteins to stop it from replicating inside a host cell. These antivirals are highly susceptible to viral mutations; if the virus mutates and starts using slightly different proteins or mechanisms to complete its life cycle there is potential that the previously effective antiviral may become useless. On the other hand broad spectrum antivirals inhibit a broad range of viruses by exploiting the viruses dependency on the host cell. They effect the processes and other factors within the host cell which are used by the virus during the replication stage of its life cycle, by either inhibiting the pro-viral host cell factors or by the activating the host organisms innate immune response.
A collaborative study from researchers at the University of Nottingham, the China Agricultural University, the Pirbright Institute and the Animal and Plant Health Agency found that non-cytotoxic levels of thapsigargin triggers an host-centred immune response which is effective against at least three related human respiratory viruses.
They used in-vitro cell cultures and animal studies (mice) to study its activity against COVID-19, Influenza A and RSV. Whilst the studies have not reached clinical trials, early trials found that the drug suppresses the replication of these respiratory viruses by inhibiting multiple processes involved in the viruses replication.
Some of the key features which make thapsigargin a promising broad spectrum antiviral are:
- Since it is stable in acids with a pH similar to that of our stomachs it can be administered orally, which means it can be taken at home without the need for injections or hospitals.
- Not sensitive to virus resistance as it targets the host cells not the viruses.
- Several hundred times more effective than current antivirals.
- Able to stop viruses from replicating within cells for at least 48 hours after just one 30-minute exposure.
- Just as effective at blocking an infection of Coronavirus and Influence A as it is in blocking a single virus infection.
- They are effective in humans and animals, and could be adopted into a holistic ‘One Health’ approach to treat human and animal viral infections.
Professor Kin-Chow Chang of the University of Nottingham led the initial studies, and in 2021 he described the early lab results as almost “too good to be true”. Despite initial skepticism, he said that “but the more we dig into it, the more convinced we are.” He is optimistic that “All research signs so far are encouraging and point to preclinical and clinical trials in the foreseeable future,” despite admitting it “difficult to predict a time frame”.
