Small molecule combinations with 2-deoxyglucose kill cancer cells

Deoxyglucose-induced killing of cancer cells

In cancer cells, 2-deoxyglucose and ABT-263/737 kill cancer cells, leaving health tissues largely unaffected.

In clinical trials of new drugs, patient volunteers often don’t know if they’re getting the real thing or a sugar-pill placebo. But one innocuous sugar can be part of a highly effective combination-drug approach that kills a wide variety of cancer cells.

That’s the surprising result of several tantalizing recent studies that are exploring combinations of anti-cancer compounds and a version of glucose that is missing one of its six oxygen atoms. One of the most recent studies published online in the journal Cancer Research by researchers at the University of California, San Diego School of Medicine and Kyushu University Medical School reported that a drug combination including 2-deoxyglucose, didn’t harm normal healthy cells, but rapidly killed cells derived from leukemia, hepatocarcinoma, lung, breast, prostate, and cervical cancer.

“The goal of targeted therapy is to stop the growth of cancerous cells while doing little or no harm to healthy tissue,” said Guy Perkins, PhD, associate project scientist at the Center for Research in Biological Systems at UC San Diego, in a news release. “Cancer researchers are always looking for new therapies to target a variety of cancers and kill tumor cells in various stages of development.”

Cells use oxygen to break down glucose into CO2 and water with the release of energy to power cellular functions. Rapidly growing cancer cells burn glucose so quickly that they must switch to an alternative energy-producing process called glycolysis, which doesn’t require oxygen. Nobel laureate Otto Warburg was one of the first researchers to discover that cancer cells utilize glycolysis, and others discovered that their glycolytic rates were up to 200 times higher than that of their normal tissues of origin. He and others were quick to realize the potential to one day “metabolically target” tumor cells with drugs that interfere with glycolysis.

2-deoxyglucose

Tumor cells also take up 2-deoxyglucose with the same membrane-transport complex that’s used for uptake of glucose, but to a much greater degree than normal healthy tissue. Indeed, clinicians inject a radioactive form of 2-deoxyglucose to visualize malignant tumors and follow changes in tumor size during treatment.

Combinations of drug therapies involving 2-deoxyglucose, including one described by Perkins and co-author Ryuji Yamaguchi, a senior researcher at Kyushu University Medical School in Fukuoka, Japan, are based on restricting cancer-cell growth by inhibiting the rate-limiting first step in glycolysis. Cancer cells that absorb 2-deoxyglucose can survive, but they’re starving.

The metabolic stress is thought to mimic dietary restriction, which correlates with lower incidence of cancers, diabetes and cardiovascular diseases. In past human clinical studies, 30-250 mg/kg 2-deoxyglucose has been used to treat stress and psychiatric disorders, prostate cancer, and glioma patients.

The 2-deoxyglucose has a second impact on cancer cells. It directly affects a pro-apoptotic protein called Bak. The lethal Bak protein is normally held firmly in check in all cells, sequestered like a pearl between two proteins that act like the opposing shells of an oyster. But 2-deoxyglucose causes the disassociation of one of the protein shells (made of the Mcl-1 protein), resulting in those cells being “primed” for apoptosis if the other shell were removed.

ABT induces the second half of the shell (made of a protein called Bcl-xL) to disassociate from Bak, and apoptosis then passes “the point of no return” resulting in the death of the cancer cell.

At the same time, several experiments have shown that the anti-apoptotic protein Bcl-2 dramatically enhanced the survival of 2-deoxyglucose-treated cells. In fact, Bcl-2 activity is frequently elevated in cancer cells, causing drug resistance.

However, in another step in the direction of metabolic targeting, derivatives of ABT-737 have been found to antagonize the activity of anti-apoptotic protein Bcl-2. Those derivatives are in early-phase clinical trials. “Exploring mechanisms and determining the optimum exploring mechanisms and determining the optimum combined modality therapies involving these drugs is potentially of great clinical significance,” wrote Charles M. Knudson, Associate Professor of Biochemistry at the University of Iowa, and his co-authors in a paper in the Oct. 10, 2011, issue of Oncogene.

A September 19, 2011, report in PLoS ONE documented that when 2-deoxyglucose was injected into animals, it accumulated predominantly in cancer cells. “Thus we discovered a way to target cancer cells in animals by simply injecting deoxyglucose before the injection of ABT,” Perkins and Yamaguchi wrote in Cancer Research.

Healthy brain cells also are highly glycolytic, like cancer cells, but Perkins and Yamaguchi said those cells are protected because ABT doesn’t cross the body’s blood-brain barrier.

“The vast potential of ABT became apparent when we realized that by pre-incubating cancer cells with deoxyglucose, we could induce apoptosis in a variety of cancer types at submicromolar concentration of ABT,” Perkins and Yamaguchi wrote in the Cancer Research article.

San Francisco-based Threshold Pharmaceuticals has sponsored a Phase I Trial of 2-deoxyglucose alone and in combination with Docetaxel in patients with advanced solid malignancies. A pre-clinical study by Threshold and its collaborators published in 2004 in Cancer Research reported that 2-deoxyglucose significantly increased the efficacy of Doxorubicin and Paclitaxel, widely used conventional chemotherapeutic agents, in mouse models of osteosarcoma and lung cancer.

The 2-deoxyglucose molecule has a positive effect on cancer cells that seems to counter its negative impacts: 2-deoxyglucose activates the insulin-like growth factor receptor (IGFR), which activates a pro-survival pathway. This feature offers another metabolic target to further enhance the apoptotic killing of cancer cells with an even more potent combination of drugs.