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Title: A study on the anti tumor activity of LY303511, an inactive analogue of a P13k inhibitor, LY294002
Authors: POH TZE WEI
Keywords: H2O2, sensitization, apoptosis, vincristine, TRAIL, LY
Issue Date: 2-Apr-2007
Citation: POH TZE WEI (2007-04-02). A study on the anti tumor activity of LY303511, an inactive analogue of a P13k inhibitor, LY294002. ScholarBank@NUS Repository.
Abstract: While chemotherapeutic agents target abnormal signalling pathways in cancer in an attempt to induce death, the drug resistant nature of many tumors has resulted in a need for novel compounds that could either induce death in these resistant phenotypes or sensitise them to current drug treatments. This current study was initiated from the observation that inhibition of PI3K in tumor cells by the PI3K inhibitor LY294002 (LY29), appeared to result in intracellular H2O2 generation. However, the ability of its inactive analogue LY303511 (LY30) to also generate H2O2 in tumor cells proved that H2O2 generation was not related to any inhibition of PI3K. Further studies demonstrated that LY30 was able to enhance apoptotic sensitivity of prostate carcinoma cells to vincristine via its generation of intracellular H2O2 by augmenting caspase activation and DNA fragmentation. LY30a??s novel PI3K-independent anti tumor activity implied that there were potential side effects associated with the use of LY29 and also further corroborated the role of H2O2 as an apoptotic effector. The proven physiological significance of intracellular generation of H2O2 by the LY compounds could also account for their various reported PI3K independent effects in current literature, given the ability of H2O2 to affect cellular physiology in a pleiotropic manner. Intriguingly, the activity of LY30 was not purely restricted to its generation of intracellular H2O2. LY30 could also sensitize cervical carcinoma cells to TRAIL mediated apoptosis via enhanced signaling of the TRAIL receptor, DR5, at the cell surface. The anti tumor activity of LY30 in these different apoptotic models also indicates further potential for other LY30 like small molecules in enhancing tumor cell sensitivity to current chemotherapeutic regimens.
Appears in Collections:Ph.D Theses (Open)

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