A team comprising of Russian scientists from Moscow Institute of physics and technology (MIPT), the Institute of Developmental Biology (RAS), N.D. Zelinsky Institute of organic chemistry (RAS) along with the Institute of Cell Biophysics (RAS) has come to the conclusion of finding a better and a novel approach towards using innovative agents for anticancer activity. A synthesis of the agents is dependent upon the compounds which have been extracted from the seeds of parsley and dill.
According to MIPT Prof Alexander Kiselev, there was a need for improving the existing therapy as well as searching for new innovations to treat cancer. The combined team has been able to develop a method that results in producing antimitotic agent Glaziovianin A along with its structural analogues which has the capability to suppress further growth of the tumor cells with the help of the building blocks in its nature. Further evaluation of these agents with the use of validated sea urchin embryo assays has yielded several candidates which would affect the tubulin dynamics.
Presently, the primary method for the treatment of cancer is via chemotherapy. This method comprises of antimitotics, which inhibits the growth of the cancer cells by forming a blockage for mitosis, the process of cell division.
Cancer cells tend to divide very frequently, at an alarming rate when compared to the normal cells, and are hence more susceptible to such antimitotics. As an example, an unchecked melanoma cell will double up every three days, whereas the healthy progenitors melanocytes increases by 15%, even when there is stimulation in the cell division. A very important part in mitosis is played by microtubules. They are mostly composed of a protein aka tubulin.
It is the antimitotics that binds tubulin, affecting the dynamics and disrupting the cell cycle, which eventually results in the rest of the cell division, and subsequently the selective death. This study is focused upon the potent antimitotic agent, also known as Glaziovanin A, which is isolated from the Ateleia glazioviana Baill, a tree commonly found in Brazil.
The subsequent synthesis of this particular agent is a time-consuming task and requires a lot of precursors as well as catalysts which are very expensive. The author of the paper tends to produce a better and a novel approach towards achieving an even better six-stage synthesis process, rather than the nine stages for the extraction of Glaziovianin A. The precursors for this process will be derived from the seeds of parsley and dill.
In addition to the Glaziovianin A, other structural analogues have been synthesized in order to help find out the favorable antimitotic properties. It is the anti-tumor activity which was tested with two independent methods, making use of the sea urchin embryos as well as the human cancer cells.
The embryos of the sea urchin were effectively used to mimic the dividing tumor cells which were defenseless against the dynamics of tubulin. Additional tests to an aqueous medium were done by the scientists, to determine the concentration at which the division rate changes, and comes to a total stop. The author of the study mentioned that the division is always disrupted due to the specific antibulin activity found within an agent; the embryos of the sea urchins would start spinning axially. This effect was found when observations were done through a common light microscope.
With the use of sea urchin embryos, scientists were able to figure out several important parameters essential for an anti-cancer molecule to strike that “bull’s eye” shot. These include a specific antimitotic effect, overall toxicity, solubility and biomembrane permeability.
To confirm this particular anti-tumor effects, tests were done with a variety of different human cancer cells, particularly melanoma, breast, ovarian cancer and lung cancer. The results of the experiment show that the test subjects were pretty effective in limiting the growth of the melanoma cells and showed no additonal toxicity to healthy blood cells. The detailed structural activity relationship studies in both these tests have converged to the use of the Glaziovianin A to be known as the most active anti-tubulin agent.
Future studies will focus on optimizing this compound to improve its metabolic stability and solubility and additional xenograft studies in mice to verify anti-tumor activity and clinical development potential.
The complete study has been published in the reputable Journal Of Natural Products.