Peptide Reverses Temozolomide Resistance in Glioblastoma Cells

Scientists have discovered how to sensitize drug-resistant human glioblastoma cells to chemotherapy. Their findings were published in Cancer Research (doi:10.1158/0008-5472.CAN-15-1286).

Glioblastoma accounts for almost half of all brain cancers. Fewer than 1 in 20 patients survive 5 years after diagnosis, and treatment involves surgical removal of the cancerous tissue, followed by chemotherapy.

The treatment, although aggressive, typically improves a patient's survival rate from 12 months to only 14.5 months.

"The grim fact that an increase of only 2 and a half months represents a significant improvement in survival for glioblastoma patients highlights the urgent need for better treatments," said co-corresponding author Zhi Sheng, PhD, an assistant professor at the Virginia Tech Carilion Research Institute in Roanoke, Virginia.

Patients with glioblastoma often develop a resistance to the principal chemotherapy agent, temozolomide (TMZ). The drug targets quickly replicating cancer cells and lethally damages their DNA, causing the cancer cells to destroy themselves.

"It's an effective treatment, until it's not," said cocorresponding author Robert Gourdie, PhD, director of the Virginia Tech Carilion Research Institute's Center for Heart and Regenerative Medicine Research. "Glioblastoma cells quickly become resistant, and the treatment stops working. We've known for years that this happens, and only now are we beginning to understand why."

The scientists found that, compared with healthy brain cells, human glioblastoma cells have 6 to 14 times the amount of the protein connexin 43.

"The higher the connexin 43 levels, the quicker the cancer cells become resistant to TMZ," Gourdie explained. Gourdie first encountered connexin 43 while doing heart research. Connexin 43 facilitates cell signaling, but signaling can become overactive in cells damaged by trauma or disease.

Gourdie and his research team developed a peptide called aCT1 (pronounced act one) to inhibit connexin 43-caused overactivity. The result was damaged tissue healed more quickly, with lower amounts of inflammation and scarring.

The researchers formed a company, FirstString Research Inc, to further develop the peptide as a treatment for chronic, slow-healing wounds, such as diabetic foot ulcers and venous leg ulcers.

The scientists wondered whether the same inhibition of connexin 43 would allow cancer cells that had grown resistant to TMZ to recover their sensitivity to the drug. So the researchers administered a combination treatment of aCT1 and TMZ to human glioblastoma cells surgically obtained by neurosurgeon Gary Simonds and his team at Carilion Clinic.

"In every instance, the cells began to respond to TMZ again," said Sheng, who is also an assistant professor of biomedical sciences and pathobiology at the Virginia-Maryland College of Veterinary Medicine. "The combination of aCT1 and TMZ caused a striking recovery in sensitivity to the treatment."

Not only were the tumor cells resensitized to the combined TMZ treatment, but so were the individual cancerous stem cells. Glioblastoma stem cells are particularly dangerous for patients because they migrate in the brain and become hidden.

"Administering aCT1 with TMZ could provide a powerful new therapy for glioblastoma and other cancers," Sheng said. "A National Institutes of Health-supported, basic science study of how cells talk to each other led to a potential treatment for the deadliest brain cancer, and it might aid in treating several other cancers."

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