Etoposide : This is used in chemotherapy to prevent cell division and works by causing mutation in the dividing cell since cancer cells divide more rapidly than a normal cell. It works by binding to the DNA-Topoisomerase complex which causes transient double stranded breaks to help uncoil DNA during cell division. In normal cells, the DNA-Topoisomerase-II complex breaks the double stranded DNA, allow the DNA strand to go through and then religate the double strand back. However, when Etoposide binds to the complex, it prevents the repair of DNA. Not only that, but it remains bound to the complex and thus locks up Topoisomerase-II. This causes the double stranded breaks to continue building up while at the same time locking up the topoisomerase so that it is not available somewhere else within the cell.
There are specific sensors inside the cell that sense DNA damage such as p53 or ATM/ATR kinases (ATM is primarily activated by double-stranded DNA breaks). Since tumor cells usually lack p53, they cannot respond to the ectoposide effect vs normal cells. Once the double stranded breaks increase, they cause increase in apoptotic pathways (both p53 dependent and independent) leading to the death of the cell.
The history of etoposide is interesting. It is gylcoside derivative of podophyllotixin from the rhizome of the mayapple. Another drug that is similar to it is teniposide. The Mayapple has been used in traditional medicine by indigenous people in removing warts (escharotic) and the active ingredient Podophyllin and salicyclic acid has also been used to treat plantar wart.
Now interestingly, the same etoposide has been used to cause mutations in plants to create new varieties. The paper recently published in PLOS Genetics (https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1011977) uses Etoposide to cause mutations and develop new varieties of plant species. The usual method was to use radiation but now the chemical method generates new mutants and then selection of the mutant helps in finding the right species that is of interest. This is not specific mutation so a screening effort is needed to find the specific plant of interest.
This highlights the diversity of chemicals in plants and how they can also affect each other.
