Oesophageal Cancer Research – Assoc Prof Denver Hendricks (Marine natural products)
Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town
Title of the project
Marine natural products as drug leads for oesophageal cancer chemotherapy (project ended 31 March 2010)
Highlights of the project
In 2008 we extended the evaluation of a group of synthesised analogues of the KLM compounds initially described in 2007. One of the structures (SNS05-044-1C) displayed IC50 values (3-6uM) similar to the IC50 values (4-6uM) originally observed for KLM155. Sensitivity to the cytotoxic effects of SNS05-044-1C were observed in two oesophageal cancer cell lines (WHCO1 and KYSE450).
Our preliminary results indicate that this compound induces apoptosis as measured using PARP cleavage nalysis. A related compound (SNS05-041-1C) was also prepared and was isolated as a racemic mixture. Our collaborator invested a great deal of time to separate the two enantiomers of this compound, which we tested for activity against oesophageal cancer cell lines.
Our results indicated hat the racemic mixture (SNS05-041-1C) and the separated enantiomers (SNS06-055-1B and SNS06-55-1B) displayed similar toxicity toward oesophageal cancer cell lines. Our initial interpretation is that the functional group located on the chiral center is probably not directly involved in the reactions leading to cell death (although further work will be required to strengthen this argument). Additional atches of these compounds are currently being re-synthesised for further analysis.
In addition, we examined more analogues of Lapachol, similar in structure to 2-deoxylapachol, which we had previously reported on. Of the three structures analysed, only one of the analogues (blapachol) isplayed high activity against oesophageal cancer cell lines (IC50 = 1.6uM). These results re reproducible, and the effects of this compound on apoptosis and activation of cell signalling networks are currently being evaluated.
How was this project of value in the struggle against cancer?
In this project we have examined the potential of synthetic analogues of the KLM series of compounds to block the proliferation of oesophageal cancer, and induce apoptosis. These results show that these analogues of KLM also induce apoptosis in oesophageal cancer cell lines like the KLM compounds, and should be investigated further, to understand the mechanism of action of these compounds.
This had been difficult to determine before, considering the small amounts of compounds that had reviously been isolated from marine organisms.
Furthermore, I currently have an MSc student (Ms. Nelusha Shunmoogam-Gounden) who has been working on this project for the past two years (2008 and 2009). I anticipate that she will upgrade her registration to a PhD at the end of 2009. This student (Indian female) has made significant progress in her project, and I fully expect her to complete her PhD by the end of 2011. In this regard, I think we have made significant progress in training a Black female South African, who should be in a position to operate as an independent biomedical researcher by the end of her training, and who will contribute to the fight against the burden of disease, particularly cancer in South Africa.
Future plans with the project
Our next step would be to further characterise the signalling pathways activated by the compounds described above, to better understand how cell death is initiated. We would also be interested to determine the sensitivity of cells to these compounds in cells in which proliferative and survival signals had been compromised.
- van Wyk AW, Gray CA, Whibley CE, Osoniyi O, Hendricks DT, Caira MR, Davies-Coleman MT. (2008). Bioactive Metabolites from the South African Marine Mollusk Trimusculus costatus. J Nat Prod.;71(3):420-5.
- Catherine E Whibley, Kerry L McPhaiul, Robert A Keyzers, Michelle F Maritz, Virna D Leaner, Michael J Birrer, Michael T Davies-Coleman and Denver T Hendricks. (2007) Reactive oxygen species mediated apoptosis ofesophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones. Mol Cancer Ther. 6 (9):2535-43.
- Mann MG, Mkwananzi HB, Antunes EM, Whibley CE, Hendricks DT, Bolton JJ, Beukes DR.. (2007). Halogenated monoterpene aldehydes from the South African marine alga Plocamium corallorhiza. J Nat Prod. 2007 Apr;70(4):596-9.
- Suthananda N. Sunassee, Albert W. W. van Wyk, Omolaja Osoniyi, Denver T. Hendricks, Michael T. Davies-Coleman. (2007) Synthesis and Cytotoxicity of Analogues of the Marine Secondary Metabolite, 2-Deoxylapachol.J. Chem. Res. 12:677-679
- Oesophageal cancer research