Smac mimetics as new cancer therapeutics

Abstract

The recent discovery of Smac and the elucidation of its structure and function have led to the rapid development of Smac mimetics, comprising Smac derivative and mimicking molecules, for use in cancer treatment. Smac is an endogenous proapoptotic protein that resides in the mitochondria and is released when a cell is triggered to undergo programmed cell death. One of the mechanisms by which Smac promotes apoptosis is through its ability to inhibit inhibitors of apoptosis (IAPs), by direct inhibition and/or proteasomal degradation of some members of the IAP family, and therefore disinhibit caspases. Thus, the use of Smac mimetics as anticancer agents follows a rational approach in cancer therapeutics. This approach directly targets dysregulated, neoplastic cells that overexpress IAPs or underexpress Smac. Although Smac mimetics are able to elicit an anticancer response when used alone, these molecules can also function effectively and synergistically when combined with other therapeutic agents. A variety of Smac mimetic types comprising peptides, polynucleotides, and compounds have been studied both in vitro and in vivo. This discussion addresses the current status of Smac mimetics in cancer research.

IAPs: Guardians of RIPK1

“…2 Consistent with the notion that different types of cancer cells are addicted to IAPs for their survival, inactivation of IAPs, particularly when combined with other treatments, results in the death of many tumour cells. 3 While it is clear that IAPs are frequently deregulated in cancer, less clear is how these versatile E3 ligases mediate their pro-tumourigenic effects.…”

Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma

“…The combination of Smac activation with classical anticancer drugs seems to be a rational therapeutic approach (15,16). Overexpression of Smac and chemically synthesized Smac mimetics can enhance apoptosis induced by chemotherapy and radiotherapy in several types of tumor cells (12,13,(17)(18)(19)(20)(21).…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…Indeed, alterations in IAP and Smac proteins have been associated with chemoresistance and poor prognosis in cancer (Hunter et al, 2007;Zeng et al, 2010) and Smac mimetics can sensitise various chemotherapyresistant tumour cells to cisplatin, doxorubicin and TRAIL in vitro and in vivo (Chen and Huerta, 2009). The ability of Smac mimetics to stimulate apoptosis or necroptosis makes them ideal for targeting cancers that may be defective in either of the cell death pathways.…”