Characterization of a Small Molecule Smac Mimetic's Role in Inducing Apoptosis in Human Cancer Cells

Date

2008-09-19

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Yalcin-Chin, Asligul

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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.

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