Researchers discovered how a drug-lead compound kills cancer cells by 'starving' them of energy, hence preventing tumour formation.
A team of scientists from the National University of Singapore's (NUS) Department of Biological Sciences and Mechanobiology Institute have discovered how a drug-lead compound -- a compound that is undergoing preclinical trials as a potential drug -- can deprive cancer cells of energy and stop them from growing into a tumour. This drug-lead compound is named BPTES.
This is the first time a research group has provided evidence showing how a drug-lead compound suppresses tumour formation.
Building on the new findings, the NUS team also derived positive results for a novel dual-drug treatment regime involving BPTES that kills kidney and breast cancer cells more effectively.
The team led by Associate Professor Low Boon Chuan and Associate Professor Jayaraman Sivaraman first published their findings in the Proceedings of the National Academy of Sciences (PNAS) on 26 April 2012.
Killing cancer cells by 'starving' them of energy
Classic experiments in cancer biology have demonstrated that cancer cells feed off the breakdown of the amino acid glutamine to gain energy and grow into a tumour. While it is known that human glutaminase is the first enzyme in catalysing this series of biochemical reactions, little is known about how its activity is controlled, and how it can be manipulated.
The NUS research team has successfully identified the mechanism in which the BPTES that can bind and inhibit glutaminase, can effectively starve the cancer cells of their energy source, and hence, could potentially prevent tumour growth.
In addition, the team has also found that the glutaminase activity can be activated upon the addition of phosphate by epidermal growth factor signaling a pathway that controls cancer cells proliferation. By using another inhibitor to block the kinase Mek2 within this cancer-causing pathway, coupled with the use of BPTES, the combined therapeutic effect is more potent and less toxic. This raises the hope of offering a new dual-drug cancer treatment regime for cancers such as lymphoma, prostate, glioblastoma, breast and kidney cancer cells that is more effective and with less side effects.
The Next Step
Armed with structural insights into the binding and signaling pathway that activates glutaminase, the NUS research team is conducting more studies to determine whether a combination of drugs would be even more effective at inhibiting glutaminase activity and hence, tumour formation.
Using the knowledge that they gained through the current studies, the research team will also look into optimising the tumour suppression property of BPTES to increase its efficiency and lower its side-effects.
- K. Thangavelu, C. Q. Pan, T. Karlberg, G. Balaji, M. Uttamchandani, V. Suresh, H. Schuler, B. C. Low, J. Sivaraman. Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. Proceedings of the National Academy of Sciences, 2012; 109 (20): 7705 DOI: 10.1073/pnas.1116573109
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