Okaro, Maduabuchi;
(2004)
Anti-apoptotic proteins and cholangiocarcinoma.
Masters thesis (M.S), UCL (University College London).
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Abstract
Cholangiocarcinoma is refractory to treatment by chemotherapy and radiotherapy, which exert their effects on tumour cell growth mainly through the induction of apoptosis. The factors responsible for the poor response of this disease to the apoptosis inducing effect of chemotherapy and radiotherapy are unknown. Members of the Bcl-2 family of proteins play a central role as intracellular regulators of apoptosis. In vitro and in vivo studies have identified that in certain malignancies the expression by tumour cells of these mitochondrial targeting antiapoptotic proteins provide a survival advantage to these cells. The expression of these proteins by cancer cells may also reduce their response to cytotoxic therapy. The hypothesis of this thesis is that resistance to apoptosis may be one of the factors responsible for the poor response of cholangiocarcinoma to treatment, which may be a consequence of mitochondrial targeting antiapoptotic proteins. In the first section of the study, the expression of the antiapoptotic proteins Bcl-2, Mcl-l and BC1-XL was examined in 30 resected cases of cholangiocarcinoma, and 3 human cholangiocarcinoma cell lines using immunohistochemical and immunofluorescent techniques. In all the cholangiocarcinoma specimens examined, Mcl-l and BC1-XL proteins were co- expressed by the majority of the malignant cell population. Bcl-2 protein was not however detected in any of the specimens. This confirmed that antiapoptotic proteins are expressed by cholangiocarcinoma cells but provided no information on their biological effects. The second section analysed the kinetics of apoptosis in human cholangiocarcinoma cells after exposure to the therapeutic agents chemotherapy. X-ray and also UV irradiation to test the hypothesis that cholangiocarcinoma cells are resistant to cytotoxic therapy induced apoptosis. Human cholangiocarcinoma cell lines were incubated with various concentrations of chemotherapy drug or exposed to various doses of radiotherapy. The apoptotic responses were then monitored over a 96 hour period post treatment and then dose response graphs constucted. Cholangiocarcinoma cells were found to be resistant in vitro to chemotherapy and radiotherapy induced apoptosis. Finally, Pklll95 and diamide, drugs which target the mitochondria and functionally counteract antiapoptotic Bcl-2 proteins, were used to test the hypothesis that the inhibition of antiapoptotic proteins can increase the sensivity of cholangiocarcinoma cells to therapy. Experiments were carried out both in vitro and in vivo (xenografts on SCID/NOD mice). This study confirmed that in the presence of the Bcl-2 antagonists cholangiocarcinoma cell apoptosis was increased following chemotherapy and radiotherapy. This demonstrates for the first time an association between the expression of antiapoptotic proteins BC1-XL and Mcl-l and the susceptibility of cholangiocarcinoma cells to apoptosis. The work contained in this thesis demonstrates that human cholangiocarcinoma cells express the antiapoptotic proteins Mcl-l and BC1-XL and are resistant to chemotherapy and radiotherapy induced apoptosis. Antagonising the function of these proteins increases the sensitivity to both chemotherapy and radiotherapy in both cell cultures and an animal model. Inhibitors of the antiapoptotic proteins should be further investigated for their use in conjunction with conventional cytotoxic therapy for the treatment of CCA and may be of value in the treatment of other cancers.
| Type: | Thesis (Masters) |
|---|---|
| Qualification: | M.S |
| Title: | Anti-apoptotic proteins and cholangiocarcinoma |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Health and environmental sciences; Cholangiocarcinoma |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10104184 |
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