There has been little Dasatinib Sigma work, however, to establish whether antagonists of endog enous anti apoptotic proteins, such as IAPs, can improve the efficacy of targeted therapies for breast cancer. In the present article we conduct proof of principle studies to determine whether IAPs contribute to the apoptosis resistance of breast cancer cells to TNF Inhibitors,Modulators,Libraries related apoptosis inducing ligand and ErbB antagonists. Apoptosis mainly occurs through one of two pathways, the extrinsic pathway or the intrinsic pathway. The extrinsic path way is activated by death ligands such as TRAIL, while the intrinsic pathway occurs in response to cell stresses such as growth factor withdrawal or DNA damage. Following activa tion of either apoptotic pathway, the caspase Inhibitors,Modulators,Libraries family of pro teases execute cells through their proteolytic activity.

IAPs can in turn negatively regulate caspases, blocking apoptosis. XIAP is the most potent caspase inhibitor in the IAP family, it binds to and inhibits active caspases 3, 7 and 9, and additionally ubiquitinates them. Two further IAPs, cIAP1 and cIAP2, also bind caspases but do not directly inhibit Inhibitors,Modulators,Libraries them, instead inducing their proteasomal degra dation. The IAPs themselves are controlled at several levels, including the release of a pro apoptotic factor second mitochondrial activator of caspases from the mitochondria during apoptosis. Smac displaces caspases from XIAP, thereby pre venting the inhibitory function of XIAP and promoting caspase activity. The cIAPs achieve part of their anti apoptotic function by binding to and ubiquitinating Smac, freeing XIAP to suppress caspase activity.

Since IAPs and their regulators act in a concerted manner dur ing apoptosis, their dysregulation can increase the threshold for apoptosis in cancer, thereby contributing to disease pro gression. For example, Survivin is normally only expressed during mitosis in adult cells, but is dramatically upregulated Inhibitors,Modulators,Libraries in many cancers leading to a poor prognosis for recurrence free survival. Overexpression of the other IAP family mem bers in cancer also occurs but is not as clearcut as for Sur vivin. XIAP is ubiquitous in normal tissues, and is elevated in some cancers including renal, acute myeloid leukaemia and bladder cancer. The correlation between elevated XIAP levels and clinical outcome, however, is not straightfor ward since its overexpression correlates with disease severity in acute myeloid leukaemia but not in lung cancer or prostate cancer.

There are less Inhibitors,Modulators,Libraries data on cIAPs, although chro mosomal currently amplification of 11q21 q23, which encodes both cIAP1 and cIAP2, is observed in oesophageal squamous cell carcinomas and cIAP2 activating translocations can occur in some B cell lymphomas. cIAP1 also has oncogenic potential, as it has the ability to transform liver cells into hepatomas in combination with the oncogene Yap.