Synthetic compound promotes death of lung-cancer cells, tumors

The findings, appearing in today’s issue of Cancer Cell, suggest that the compound might one day be used in targeted therapies for lung and possibly other cancers, the researchers said.

“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 Dr. Xiaodong Wang, professor of biochemistry at UT Southwestern and senior author of the study.

In 2000, Dr. Wang announced the discovery of a cellular protein called Smac, which plays a key role in the normal self-destruction apparatus present in every cell. This process, called apoptosis, is activated when a cell needs to be terminated, such as when a cell is defective or becomes unnecessary during normal growth and development. In cancer cells, the self-destruct mechanism is faulty.

In 2004, Dr. Wang and his colleagues developed a compound that mimics the action of Smac. They found that in cell cultures, the compound killed cancer cells but left healthy cells unaffected. In those studies, however, the Smac mimic only killed cancer cells when it was introduced along with another molecule often involved in the cell-death machinery, called tumor necrosis factor-a, or TNFa.

In the current study, Dr. Wang’s research group tested 50 human non-small-cell lung-cancer cell lines in culture and found that 22 percent of them were sensitive to the Smac mimic alone, without having to add TNFa. The researchers also found that the Smac mimic alone was effective against some types of breast cancer and melanoma cells in culture.

“The apparent ability of a Smac mimetic, as a single agent, to induce cell death in nearly one-quarter of lung-cancer cell lines tested was quite remarkable,” said Dr. Wang, who is a Howard Hughes Medical Institute investigator at UT Southwestern.

The researchers then introduced those sensitive cancer-cell lines into mice, where they grew into tumors. When the lung-tumor-bearing mice were injected with the Smac mimic, the tumors reduced significantly in size, and in some cases, the tumors disappeared completely.

Also tried was a similar experiment treating breast-cancer tumors in mice with the Smac mimic alone. That treatment, however, showed little effect.

The researchers then investigated what made those particular lung-cancer cell lines so sensitive to the Smac mimic alone.

“We found that these sensitive cell lines produce their own TNFa,” Dr. Wang said.

In addition to aiding in cell death, TNFa also is known, paradoxically, to sometimes play a role in aiding cancer-cell survival and growth. In combination with the Smac mimic, however, the role of this molecule is clear: cell death.

“The Smac mimetic is able to exploit certain cancer cells that secrete TNFa and usurp this pro-survival signal to promote cell death,” Dr. Wang said.

“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 TNFa.”

Additional research and tests will be needed before the Smac mimic is tested in humans, Dr. Wang said, adding that detecting the presence of TNFa in a patient could serve as a marker to indicate that the cancer might be sensitive to treatment with the Smac mimic alone.

“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,” he said. “Because this compound affects cancer cells selectively, it could combat this problem.”

Source: UT Southwestern Medical Center

Key Event in Cell Death Occurs as Single, Quick Event
Scientists at St. Jude Children's Research Hospital have demonstrated that a key event during apoptosis (cell suicide) occurs as a single, quick event, rather than as a step-by-step process. Apoptosis eliminates extraneous cells from the developing body; and disposes of cells that sustain irreparable harm to their DNA or are infected with microorganisms.
Mayo researchers explore issues related to multiple myeloma treatment
Multiple myeloma (MM) is a cancer of plasma cells that affects approximately 3 in 100,000 people each year. Although there is no cure for this disease, researchers have developed treatments that help relieve pain, control complications, and slow the progress of MM in many patients. Unfortunately, some of the most effective therapies also have toxic side effects that can pose serious health risks and reduce quality of life. In the October issue of Mayo Clinic Proceedings, two articles authored by Mayo researchers address the issue of how to balance the risks and benefits associated with MM treatments.
Bioengineers fill holes in science of cellular self-organization
The chemical and biological aspects of cellular self-organization are well-studied; less well understood is how cell populations order themselves biomechanically – how their behavior and communication are affected by high density and physical proximity. Bioengineers and physicists at the University of California San Diego, in a paper published in the current issue of the Proceedings of the National Academy of Sciences, have begun to address these fundamental questions.
Early-stage gene transcription creates access to DNA
A gene contained in laboratory yeast has helped an international team of researchers uncover new findings about the process by which protein molecules bind to control sequences in genes in order to initiate gene expression, according to findings reported in the journal Nature.
Landmark discovery of 'engine' that drives cell movement
This research by Thomas Leung, Ph.D., and his team in the GSK-IMCB Group at the Institute of Molecular and Cell Biology (IMCB), under Singapore's Agency for Science, Technology and Research, is fundamental to the understanding of how assembles its internal machinery required for cell movement.
Battling cancer, one cell at a time
New research suggests that the identification and examination of key cell signaling events required for initiation and progression of cancer might be best accomplished at the single cell level. The research, published by Cell Press in the October issue of the journal Cancer Cell, provides new insight that may lead to better diagnosis and treatment of some complex cancers.
New Stanford diagnostic test for rare leukemia appears to give faster results, study finds
A new twist on a well-known cell sorting technique may allow physicians to diagnose rare leukemias in hours instead of weeks, according to a study by researchers at the Stanford University School of Medicine and UC-San Francisco. The clinical promise of the Stanford-developed approach, which eavesdrops on individual cells to decipher potentially dangerous molecular conversations, is likely to extend to many other disorders in which cell-signaling pathways are disrupted.
Surface tension drives segregation within cell mixtures
What does a mixture of two different kinds of cells have in common with a mixture of oil and water? The same basic force causes both mixtures to separate into two distinct regions.

Synthetic compound promotes death of lung-cancer cells, tumors

Related stories:

News discussion: