Characterization of small molecule smac mimetric's role in inducing apoptosis in human cancer cells

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Title: Characterization of small molecule smac mimetric's role in inducing apoptosis in human cancer cells
Author: Yalcin-Chin, Asligul
Abstract: Inhibitor of apoptosis proteins (IAPs ) regulates apoptosis by inhibiting caspases . This inhibition mechanism is an escape from death used by some human cancers . Second mitochondria -derived activator of caspases (Smac ) , a mitochondria -released protein during apoptosis , binds to IAPs BIR domains with four amino acid residues (AVPI ) and releases the inhibition caused on caspases by IAPs . With the idea of designing a Smac mimicking drug , that will induce apoptosis in cancer cells , we synthesized a small molecule Smac mimetic compound . I tested the ability of the Smac mimetic compound to induce apoptosis on several human cancer cells in combination with chemotherapeutic agents . Unexpectedly , in 25 % of the cancer cells we tested , Smac mimetic treatment alone caused apoptosis . Of the cancer cells that were sensitive to Smac mimetic , MDA -MB231 human breast cancer cells and HCC44 , HCC461 , H2126 lung cancer cells had the highest sensitivity . In addition , a majority of the lung cancer cell lines I tested were sensitive to TNF and /or TRAIL in combination with Smac mimetic . We identified the target of Smac mimetic to be XIAP , cIAP1 , and cIAP2 in both Smac mimetic induced and TNF /Smac mimetic induced apoptosis . Moreover , we were able to mimic the Smac mimetic effect by triple knockdown experiments of IAPs in TNF induced cell death . Furthermore , we identified the target of Smac mimetic to be XIAP in the TRAIL pathway . This work identifies the targets and mechanism of Smac mimetic induced cell death in cancer cells .
URI: http : / /hdl .handle .net /2152 .5 /778
Date: 2009-09-19

Citation

Characterization of small molecule smac mimetric's role in inducing apoptosis in human cancer cells. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /778 .

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