An investigation into the molecular mechanisms induced by derivatives of natural products in oesophageal cancer

Current chemotherapies for oesophageal cancer display poor efficacy and tolerability, highlighting an unmet need for novel chemotherapeutic agents. Artemisinin derivatives, currently used to treat malaria, were recently shown to possess potent anticancer activity. This study investigated the potential of two first generation artemisinin derivatives (artesunate and dihydroartemisinin), together with novel artemisinin hybrid compounds, as cancer chemotherapeutic agents and explored the mechanism of action in oesophageal cancer. Artesunate and dihydroartemisinin including seventeen other artemisinin derivatives were screened against oesophageal cancer cells using the 3 - [4,5-dimethylthiazol-2 -yl]-2,5 - diphenyltetrazolium bromide (MTT) assay and GraphPad Prism Software to calculate IC 50 (50% inhibitory concentration) values. Novel halogenated artemisinin - isatin hybrid compounds displayed the best activity against oesophageal cancer cells, and were more potent than artesunate and dihydroartemisinin in a small panel of oesophageal, breast and cervical cancer cell lines tested. The novel derivatives induced a G0/ G1 cell cycle arrest whilst the parental compounds induced a G2/ M block of the cell cycle, using flow cytometry. This suggested a different mechanism of action for the novel compounds. Dihydroartemisinin and the most active novel hybrid, EXP57EA, were investigated to understand their molecular mechanisms of action in oesophageal cancer.

Grantor dc:publisher.institution

Division of Medical Biochemistry

Year dc:date.issued

2014

Author dc:creator

• Shunmoogam-Gounden, Nelusha

Advisor dc:contributor.advisor

• Hendricks, Denver

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/13237

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/13237