Exploiting the anticancer properties of plant extracts for colorectal carcinoma prevention and therapy

Colorectal carcinoma (CRC) is the third most common and second deadliest type of cancer in the world. Its incidence is higher in western world countries, where poor lifestyle habits such as unhealthy dietary regimens help increase the risk of getting the disease. The pathogenetic basis of CRC are highly heterogeneous, and mutations impacting several pathways that regulate cellular proliferation, growth, survival, migration and metabolism have been described. Surgery and chemotherapy represent the backbone of all therapeutic approaches, but targeted therapies such as immunotherapy or treatment with monoclonal antibodies can be exploited too, depending on the molecular features and stage of the tumour. However, these therapies may have variable efficacy, as mortality remains high especially for metastatic CRC, and are associated to even strong side effects. In this context, plant biodiversity can represent a huge reservoir of bioactive molecules with anticancer properties, as already a few clinically approved chemotherapeutic drugs have been isolated or derived from plant species. Therefore, in this project we tested the effect of extracts derived from different plant species on the E705 and SW480 CRC cell lines and on the CCD 841 healthy colon mucosa cell line, with the goal of finding candidates toxic only on CRC cells. Out of the 33 screened species, we selected Diospyros kaki and Gratiola officinalis and further characterised the mechanisms underlying their anticancer properties. Diospyros kaki reduces the viability of CRC cell lines at the doses of 200 and 400 μg/mL by increasing oxidative stress and disrupting mitochondrial functionality, resulting in apoptotic cell death. Gratiola officinalis decreases the viability of the E705 CRC cell line at the 50 and 100 μg/mL concentrations, whilst impacting the SW480 cell line only at the 100 μg/mL dose. Contrary to what is observed in Diospyros kaki, where the extract causes the same effects in both CRC cell lines, Gratiola officinalis acts differently on the E705 and SW480 cell lines. Specifically, it reduces cellular proliferation, induces apoptosis and deregulates the glycolytic metabolism in the former, while it arrests cell cycle progression in the G2/M phase in the latter. Analysing the chromatogram of the whole Gratiola officinalis extract, we identified verbascoside as the candidate molecule responsible for the anticancer properties of the extract and we tested it on an extended panel of CRC cell lines to assess its impact on cell viability. In conclusion, this thesis remarks the important value of plant biodiversity with respect to CRC prevention and therapy, proposing Diospyros kaki and Gratiola officinalis as new, relevant players in this setting.