One of the major challenges associated with cancer therapy is the acquisition of chemoresistance by tumour cells. Many novel therapeutic approaches to overcome chemoresistance have involved targeting specific signalling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study sought to determine the effect of PI3K inhibition on the resistance of human cancer cells to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in resistance to doxorubicin, etoposide, 5-fluorouracil, and vincristine in breast (MDA-MB-231) carcinoma cells as determined by clonogenic assays. Increased survival following PI3K inhibition was also observed in prostate (DU-145), colon (HCT-116) and lung (A-549) carcinoma cell lines exposed to doxorubicin. Drug resistance mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G1 phase of the cell cycle. Inhibition of PI3K signalling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21Waf1/Cip1 and p27Kip1. Knockdown of p21Waf1/Cip1 expression with siRNA resulted in a significant decrease in LY294002-induced resistance. However, the effect of p27Kip1 knockdown on LY294002-induced resistance was inconclusive because of high inter-experimental variability. Furthermore, knockdown of either p21waf1/cip1 or p27Kip1 did not overtly prevent LY294002-induced cell cycle delay. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle. However, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) is a critical determinant of chemosensitivity. Since the efficiency of most chemotherapeutic agents depends on the rate of cell proliferation, delays in cell cycle progression may be an important mechanism of chemoresistance. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2008-09-24 14:00:39.679
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/1475 |
| Date | 25 September 2008 |
| Creators | Mcdonald, GAIL |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | 1123169 bytes, application/pdf |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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