Cancer cells are well known for liking the simple sugar glucose. Their elevated appetite for glucose is part of the Warburg effect, a metabolic distortion that has them sprinting all the time (glycolysis) despite the presence of oxygen.
A collaboration between researchers at Winship Cancer Institute, Georgia State and University of Mississippi has identified a potential drug that uses cancer cells’ metabolic preferences against them: it encourages the cells to consume so much glucose it makes them sick.
Their findings were published in Oncotarget.
The discovery emerges from an effort to target another critical aspect of cancer biology. When cancer cells outgrow their local blood and oxygen supply, they create a low-oxygen or hypoxic environment. The cancer cells adapt and send out signals to attract new blood vessels. HIF (hypoxia inducible factor) is key to this response; Erwin Van Meir and colleagues have published several papers on the anticancer properties of HIF inhibitors. While optimizing and testing HIF inhibitors, Van Meir and his partners found a compound named 64B that pushes cancer cells to become more metabolically deranged.
“In drug treated cells, the cells are burnt out and dying like we floor the gas pedal in a car running out of gas,” says Winship researcher Jing Chen, who has studied cancer cell metabolism extensively, but was not involved in this project.
Chalet Tan at the University of Mississippi, senior author of the Oncotarget paper, writes:
64B was initially discovered from a screening assay as an HIF inhibitor. It caught us by surprise when we realized that it accelerates the conversion of glucose into lactate (“Warburg effect”) and inhibits ATP production in tumor cells. We noticed that the culture medium of 64B-treated tumor cells became unusually yellow, a sign of excessive lactate level. It turned out that HIF inhibition by 64B is a downstream effect resulting from ATP depletion. What is unique about 64B is that, even though it is highly cytotoxic in a broad variety of tumor cells, it is safe in non-cancerous human cells. This is likely owing to distinctive glucose metabolism patterns in normal vs. tumor cells.
64B enhances rather than inhibits the Warburg effect in tumor cells, which elicits bioenergetic imbalance. Although oxidative phosphorylation in the mitochondria is generally considered to be a less critical source of ATP production in tumor cells compared to glycolysis in the cytoplasm, our results demonstrate that disrupting glucose influx into the mitochondria is detrimental to tumor cell survival.
The authors go on to combine 64B with 2-deoxyglucose, a chemical relative of glucose that interferes with its metabolism. 64B “potently suppresses tumor growth and metastasis in mouse models of triple-negative breast cancer and lung cancer,” they conclude.
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