Phytochemical, Analytical and Preclinical Investigations on Plant Extracts as Potential Antitumoural Therapy.

Date: 18 March 2015

Venue: Campus Drie Eiken, R3 - Universiteitsplein 1 - 2610 Wilrijk

Time: 2:30 PM

PhD candidate: Rica Capistrano I.

Principal investigator: Luc Pieters

Co-principal investigator: Sandra Apers

Short description: PhD defense Rica Capistrano I - Department Pharmaceutical Sciences



Abstract

Cancer is the second leading cause of death worldwide and has become the most challenging disease to cure. The burden of cancer is still increasing despite diagnostic and therapeutic advancements. The death rate due to cancer increases every year. Many of the current cancer drugs are from natural origin or derived from natural products. A plant extract is a complex mixture of different, often closely related compounds that can act on different targets. Because of the generally low concentration of these constituents, there is a low toxicity, whereas with regard to the activity often synergism is observed. In addition, the presence of prodrugs can add to the activity. Therefore medicinal plant extracts have a huge potential. In the present study several medicinal plants with previously reported cytotoxic activity and/or traditional use were investigated for their potential use against cancer.

The phytochemical investigation on the Steganotaenia araliacea Hoechst. stem bark led to the identification of spiropreussomerin A, conrauiflavonol/afzelin A and the new compound protosteganoflavanone, which have never been reported before in this plant species. In vitro studies of the S. araliacea extract resulted in a moderate cytotoxic activity for the tested cell lines. Nevertheless, protosteganoflavanone belongs to the protoflavonoids, which is considered as a promising class of anticancer compounds.

The study on the Gloriosa superba L. seeds resulted in the identification of the three main compounds, i.e. colchicine, 3-O-demethylcolchicine and colchicoside, which were then quantified using an optimised and validated HPLC-UV method. A high in vitro cytotoxic activity was observed on the tested cell lines for the G. superba crude extract. In vivo studies of the G. superba crude extract and the colchicine-poor/colchicoside-rich extract resulted in a relevant tumour growth inhibition and a significant lowered tumour metabolic activity. Furthermore, ex vivo immunohistochemical analysis of the tumour tissues showed a significant decrease in proliferation and a significant increase of apoptotic bodies. This confirms the hypothesis that indeed colchicoside can be considered as a prodrug. A combination therapy of gemcitabine together with the G. superba crude extract showed a prolongation of survival compared to the control group and a significant difference in relative tumour volume and growth over time compared to the control group and the gemcitabine monotherapy. No severe side effects or toxicity due to the treatment were observed during the entire study.

Four main benzylisoquinoline alkaloids, i.e. chelidonine, sanguinarine, chelerythrine and protopine, were identified from the Chelidonium majus L. herb extract by means of HPLC-UV. The C. majus extract showed high cytotoxic activity on certain cell lines and a preliminary in vivo study was performed to evaluate the antitumoural effect on a highly metastatic pancreatic murine model. Significantly less metastases were counted for the mice treated with C. majus extract compared to the control group. The extract, however, did not affect the weight of the primary tumours.