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Arresting cancer by energy starvation

23 May 2012

The crystal structure of a dimer of human glutaminase (orange and purple) bound to its inhibitor BPTES (cyan).
Image: Low Boon Chuan and J Sivaraman

The biological sciences research team in the X-ray laboratory: (left to right) Research Fellow Dr Pan Qiurong Catherine, PhD student Mr K Thangavelu, Assoc Prof Sivaraman (seated) and Assoc Prof Low
Cancer, a top killer, may be stopped from its deadly progression with the latest discovery by NUS researchers. They have found how a compound that is undergoing preclinical trials as a potential drug can "starve" cancer cells of energy, thus preventing them from developing into a tumour.

Assoc Prof J Sivaraman from the Department of Biological Sciences (DBS) and Assoc Prof Low Boon Chuan, who is attached to DBS and Mechanobiology Institute at NUS, have unveiled the X-ray structure of glutaminase, a key enzyme in cancer metabolism. The biologists showed that the way glutaminase binds to the chemical inhibitor BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide) can provide important understanding in the search for more effective versions of BPTES.

The investigators, in collaboration with other colleagues from NUS Department of Chemistry, Singapore's Defence Medical and Environmental Research Institute as well as Karolinska Institute, determined the mechanism whereby BPTES binds and inhibits glutaminase to cut off cancer cells' energy source, potentially blocking their growth.

The research team also established that a combination of BPTES and another inhibitor of a glutaminase-activating component would be even more effective at reducing glutaminase activity and cell growth.

These results were published in a recent issue of the journal Proceedings of the National Academy of Sciences.

"These findings could offer a new cancer treatment regime that is more potent but less cytotoxic," said Assoc Prof Low. The encouraging results show promise for a new dual-drug cancer treatment which is more effective with fewer side effects, especially for cancers such as lymphoma, prostate, glioblastoma, breast and kidney cancer cells.

The team is working on developing more inhibitors targeting glutaminase.

Click here for more information on the research.