Scientists from the Virginia Tech Carilion Research Institute and clinicians from Carilion Clinic have discovered how to sensitize drug-resistant human glioblastoma cells to chemotherapy. They published their results in Cancer Research.
Glioblastoma accounts for almost half of all brain cancers. Fewer than one in 20 patients survive five years after their diagnosis, and treatment involves surgical removal of the cancerous tissue, followed by chemotherapy.
Patients with gliobastoma often develop a resistance to the principal chemotherapy agent, temozolomide. Known as TMZ, the drug targets quickly replicating cancer cells and lethally damages their DNA, causing the cancer cells to destroy themselves.
The scientists found that, compared to healthy brain cells, human glioblastoma cells have six to 14 times the amount of a protein called connexin 43. "The higher the connexin 43 levels, the quicker the cancer cells become resistant to TMZ," said Robert Gourdie, co-corresponding author on the study.
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 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.
"In every instance, the cells began to respond to TMZ again," said Zhi Sheng, the other co-corresponding author of the paper. "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 hide from the surgeon's scalpel.
The mechanism by which aCT1 and TMZ induce sensitization remains a mystery, though.
"Our laboratory teams and collaborative partners at Carilion Clinic are continuing to study exactly how the combination treatment works," said Gourdie. "We suspect the signaling pathways are altered, and we hope our continued research will elucidate the mechanism."
The researchers believe their work could apply to other tumor types, as well. TMZ is often used as a chemotherapy agent for several other cancers, including breast and lung cancers, which can spread in the brain and become resistant to the drug.
Based on material originally posted by Virginia Tech.