Unusual three-drug combo inhibits growth of aggressive tumors

roducts within intact tumor cells using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. Software programs take this information and provide testable predictions about how these substances might drive the special metabolism of cancerous cells.

Investigating experimental mice that develop metastatic tumors of the prostate's neuroendocrine cells, the researchers discovered that the tumor cells relied on molecules that transmit signals between neurons. They found that the tumor cells respond to GABA as well as to two other neurotransmitters, glycine and glutamate.

"The question was, 'What are these neural signaling molecules doing in tumor cells found outside the central nervous system?'" says lead author Joseph E. Ippolito, a member of the University's NIH-supported M.D./Ph.D. Medical Scientist Training Program.

The researchers demonstrated that the tumor cells have receptors on their surface that recognize these neurotransmitters and are activated by them. In addition, the tumor cells directly convert GABA and glutamate into sources of energy. Moreover, glycine was involved in a mechanism that increased the amount of fatty acids - an important source of energy - in the bloodstream of the lab mice.

"We showed that the neurotransmitters GABA, glycine and glutamate not only stimulate proliferation of the tumor cells, but they also are able secure sources of energy for the cells," Ippolito says. "In a way, the tumor cells eat their own words."

Having identified a key vulnerability in these aggressive neuroendocrine tumor cells, the researchers looked for a way to exploit it. They selected agents already approved for medical use by the Food and Drug Administration.

Two drugs - amiloride, a diuretic, and carbidopa, used to treat Parkinson's disease - exert their effects by inhibiting the very same mechanisms the research group had identified as important for the tumor cells' energy-gathering reaction

Contact: Gwen Ericson
Washington University School of Medicine

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