Fireflies Help Fight Cancer: Restoring p53 Tumour Suppressor Function

Researchers at the University of Pennsylvania School of Medicine have used the luminescence from fireflies to help screen small molecules that might help restore p53 tumour suppressor gene function to cancer cells that had lost that protection through mutation.

In an attempt to defend the body, a normal p53 protein will bind to DNA during periods of cellular stress or damage. The binding of p53 to DNA initiates downstream reactions that keep the stressed cells from multiplying. Under normal conditions, p53 will activate the p21 gene, causing the cell cycle to freeze, halting cell proliferation; p53 will activate KILLER/DR5, which signals for cell death, or apoptosis. Chemotherapy and radiotherapy set out to deliberately stress tumor cells in hopes of promoting their self-destruction. Unfortunately, mutations to the p53 gene disrupt the intracellular defense system.

"Mutants of p53 that occur in human cancer fail to bind to DNA or to activate target genes, such as p21 and KILLER/DR5," explains El-Deiry, who is also the Co-Program Leader of the Radiation Biology Program at the Abramson Cancer Center at Penn. "Therefore, when cells are stressed or damaged, p53-mutant cells fail to shutdown and continue to divide uncontrollably." The development of a drug screen by El-Deiry's lab allowed the researchers to trace the activity of small molecules in p53-mutant cancer cells.

The small molecule drug screen, developed by El-Deiry's lab, was created by inserting firefly luciferase, a reporter gene capable of emitting light, into human tumor cells carrying the p53 mutation, and observing the subsequent response.

"Just as fireflies emit light that we can see with our eyes, the cancer cells were engineered to emit light if a p53-like response was triggered by any of the small molecules that we examined," explains El-Deiry.

The small molecules screened by El-Deiry's research group were obtained from the Developmental Therapeutics Program at the National Cancer Institute. The molecules represent many classes of compounds and include both natural and man-made chemicals.

"One by one, we introduced the small molecules to the p53 mutant cancer cells, which possessed the luciferase reporter gene and screened for light emissions," describes El-Deiry. The light emissions displayed by the live cell imaging instrumentation revealed which molecules were able to achieve p53 responses in the abnormal cancer cells. Further testing exposed the ability of high doses of several groups of the small molecules to kill human cancer cells in cell culture and in mouse models implanted with human tumors.

"Our work provides a blueprint for how molecularly targeted therapy can be discovered using new optical imaging technology," states El-Deiry. "This is very important going forward in the era of molecular medicine and individualized therapy for cancer patients."

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This is a clever approach to cancer drug discovery. This type of drug, if effective, could become a useful second line defense against cancer, after prevention. As cancer screens become more sensitive--able to pick up malignancies very early--the need for safe broad spectrum anti-tumour drugs such as this type of tumour suppressor gene restorer becomes greater. The key is to find such tumour suppressor gene augmentors/restorers that are both safe and effective. Good luck to the UPenn. lab.