>Magister Scientiae - MSc / Apoptosis or programmed cell death is vital to the development of organisms as they
maintain the balance between cell death and cell growth. Failure to activate apoptosis has
been implicated in carcinogenesis and often results from the over expression of anti–cancer
proteins such as the X–linked inhibitor of apoptosis protein (XIAP). XIAP is over expresses
in certain cancers and is a potent inhibitor of the initiator caspase 9 and effector caspases 3
and 7. The increased expression of XIAP in cancer cells result in the resistance to apoptosis.
The control of XIAP is therefore considered as a target for anti–cancer drug development.
Embelin or 2,5–dihydroxy–3–undecyl–1,4–benzoquinoine is a dihydroxyquinone compound
that was previously shown to inhibit XIAP. This drug was discovered by structure based
computational screening. The binding of embelin to XIAP displaces XIAP from caspases,
consequently eliminating the inhibitory effect of XIAP on apoptosis.
The objective of this study was to develop a gold nanoparticle that can be used for the
targeted delivery of embelin to cancer cells thereby enhancing pro–apoptotic effects of the
pro–apoptotic drug, ceramide. XIAP expression levels were investigated by Western blot
analysis in a panel of human cancer cell lines available in the laboratory to identify two cell
lines that can be used as low and high XIAP expression controls. Gold nanoparticles were
synthesized and conjugated with embelin and a cancer targeting peptide with the amino acid
sequence LTVSPWY. The biconjugated nanoparticles were used to co–treat MCF7 and
HepG2 cells with ceramide. Apoptosis was quantified using flow cytometry. The uptake of
gold nanoparticles was investigated using HR–TEM and ICP–OES. This study showed that
gold nanoparticles conjugated with the LTVSPWY peptide is specifically targeted to and
taken up by cancer cells. Gold nanoparticles conjugated with embelin promoted ceramide
induced apoptotic cell death of cancer cells. However, it was observed that gold nanoparticles
biconjugated with the LTVSPWY peptide and embelin failed to enhance the pro–apoptotic
effects of ceramide. iii
This study successfully demonstrated that gold nanoparticles conjugated with embelin could
be used to enhance the effects of anti–cancer drugs using ceramide as an example.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uwc/oai:etd.uwc.ac.za:11394/4251 |
| Date | January 2013 |
| Creators | Emjedi, Zaakiyah Z. |
| Contributors | Meyer, Mervin M. |
| Publisher | University of the Western Cape |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Rights | University of the Western Cape |
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