A Mimetic of the Smac/Diablo Protein May Be the Forerunner of Nontoxic Chemotherapy

Smac/Diablo is a mitochondrial protein that enables some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by ultraviolet (UV) or gamma-irradiation. The inhibitors of apoptosis (IAP) are a family of functionally and structurally related proteins, which serve as endogenous inhibitors of programmed cell death. The human IAP family consists of at least six members, and IAP homologs have been identified in numerous organisms.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) surveyed the response of a panel of 50 human non-small-cell lung cancer cell lines to a small-molecule mimetic of Smac/Diablo. Results published in the November 13, 2007, edition of the journal Cancer Cell revealed that roughly one-quarter of these lines were sensitive to treatment with the Smac mimetic alone, suggesting that an apoptotic signal had been turned on in these cells and was held in check by IAP proteins. This signal has now been identified as tumor necrosis factor alpha (TNF-alpha).

Some of the sensitive cell lines were injected into mice, which subsequently developed lung tumors. Treatment with the Smac mimic caused significant reduction in tumor size, and in some cases, complete eradication of the tumors.

"We found that certain kinds of lung-cancer cells were sensitive to this compound, which sends a signal to cancer cells to self-destruct,” said senior author Dr. Xiaodong Wang, professor of biochemistry at the University of Texas Southwestern Medical Center. "The Smac mimetic is able to exploit certain cancer cells that secrete TNF-alpha and usurp this pro-survival signal to promote cell death. Not only is single-agent Smac mimetic treatment highly effective at inducing cell death in these cell lines, but it also offers the possibility of highly specific and relatively nontoxic future therapeutic treatments by exploiting certain cancer cells' own production of TNF-alpha.”

"The challenge for cancer therapies now is that they also tend to kill normally growing cells as well as cancer cells, which results in undesirable side effects,” said Dr. Wang. "Because this compound affects cancer cells selectively, it could combat this problem.”


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University of Texas Southwestern Medical Center