Dr. Carolyn Lee-Parsons, Associate Professor of Chemical Engineering and Chemical Biology, and Dr. Erin Cram, Associate Professor of Biology, have received a $650,000 grant from the NSF to investigate the production of cancer drugs in Catharanthus roseus, also known as the Madagascar periwinkle. They hope to better understand the function of zinc finger transcription factors (ZCTs), a set of regulatory factors that influence drug production levels.
The underlying medicinal value of C. roseus crystallized when studies of the plant in the 1950s revealed a large class of nitrogen-containing molecules known as alkaloids, some of which were biologically active. Two of these compounds, vincristine and vinblastine, are presently used for treating non-small cell lung cancer, several types of lymphoma, bladder cancer, and brain cancer. Both of these compounds bind to tubulin, a key protein in mitosis, effectively interfering with rapidly dividing cancer cells.
Despite their wonder-drug status in oncology, the drugs vincristine and vinblastine are notoriously difficult to produce and isolate. Their complicated structure puts them beyond the scope of synthetic chemistry and the plants produce only trace amounts; being poisons the plant produces relatively little of the alkaloids, typically in response to herbivores and pathogen attack. The production is so miniscule that current purification methods require 15 tons of dried plant leaves for just 28 grams of vinblastine, putting the cost of production for a single kilogram at $5 million.
Furthermore, variations in plant production—from climate change, natural disaster, or contamination—reduce downstream production and make availability uncertain. Shortages of vinblastine and vincristine are so common that oncologists have alternate drug regimens prepared in the event of future availability crises.
The solution seems to lie in increasing the plant’s production of the alkaloids. That’s not a simple feat, however. These alkaloids are synthesized by over 30 steps, whereby a series of enzymes convert the starting compound one at a time, each changing it until some percentage reaches the final and desired alkaloid state.
Whether the plant produces the alkaloids in the first place relies upon the plant’s response to the environment. The plant ramps up production of alkaloids as a result of stress making it part of a larger defense response which is, notably, a shift away from growth. There’s a myriad of gene regulators pushing the plant towards one response or the other—growth vs. defense.
One group of these regulators is zinc finger transcription factors, ZCTs. These transcription factors activate a series of other, presently unknown, genes. Known as transcriptional repressors, ZCTs push the plant’s proverbial lever off, avoiding a state of high TIA production (prior research by Lee-Parsons and Cram).
The questions at hand, and the subjects of the upcoming research are: how does the plant choose between growth and defense, how do transcription factors, like the zinc finger transcription factors, get “turned on” and what are their targets? Transcriptomics, the study of large numbers of plant RNAs will assist in building a holistic understanding of the plant’s response mechanisms.
By developing and applying a systems biology approach, Lee-Parsons and Cram will further elucidate the inner workings of C. roseus. Ultimately, it may lead to the cheaper and more consistent availability of life-saving drugs.
